Azabicyclo [3.1.0] Hexyl Derivatives as Modulators of Dopamine D3 Receptors

ABSTRACT

The present invention relates to certain azabicyclo compounds of formula (I)′: 
     
       
         
         
             
             
         
       
     
     wherein the various groups are defined herein and that are modulators of dopamine D 3  receptors, e.g. to treat drug dependency, as antipsychotic agents, to treat obsessive compulsive spectrum disorders, or premature ejaculation.

The present invention relates to novel compounds, processes for theirpreparation, intermediates used in these processes, pharmaceuticalcompositions containing them and their use in therapy, as modulators ofdopamine D₃ receptors.

Recently a patent application has been published as WO2005/080382 anddiscloses the compounds of the following formula or salts thereof:

wherein

-   -   G is selected from a group consisting of: phenyl, pyridyl,        benzothiazolyl, indazolyl;    -   p is an integer ranging from 0 to 5;    -   R₁ is independently selected from a group consisting of:        halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        haloC₁₋₄alkoxy, C₁₋₄alkanoyl; or corresponds to a group R₅;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   R₃ is C₁₋₄alkyl;    -   R₄ is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or        6-membered heteroaromatic group, or a 8- to 11-membered bicyclic        group, any of which groups is optionally substituted by 1, 2, 3        or 4 substituents selected from the group consisting of:        halogen, cyano, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl;    -   R₅ is a moiety selected from the group consisting of:        isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,        thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such a group        is optionally substituted by one or two substituents selected        from: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;        and when R₁ is chlorine and p is 1, such R₁ is not present in        the ortho position with respect to the linking bond to the rest        of the molecule; and when R₁, corresponds to R₅, p is 1.

A new class of compounds which have affinity for dopamine receptors, inparticular the dopamine D₃ receptor has been found. These compounds havepotential in the treatment of conditions wherein modulation, especiallyantagonism/inhibition, of the D₃ receptor is beneficial, e.g. to treatdrug dependency or as antipsychotic agents.

The present invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein

-   -   G is selected from a group consisting of: phenyl, a 5- or        6-membered monocyclic heteroaryl group, or a 8- to 11-membered        heteroaryl bicyclic group;    -   A is a group P        wherein

P is

-   -   p is an integer ranging from 0 to 5;    -   R₁ is halogen, hydroxy, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,        C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; or corresponds        to a group R₆; and when p is an integer ranging from 2 to 5,        each R₁ may be the same or different;    -   R₂ is hydrogen or C₁₋₄alkyl;    -   n is 4, 5 or 6;    -   R₃ is selected in the group consisting of: hydrogen, halogen,        cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₃ is a phenyl group,        a 5-14 membered heterocyclic group; and any of such phenyl or        heterocyclic group is optionally substituted by 1, 2, 3 or 4        substituents selected from the group consisting of: halogen,        cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅        and haloC₁₋₄alkoxy; and wherein such haloC₁₋₄alkoxy        substituents, wherein placed in adjacent positions, may for,        together with the carbon atoms to which they're attached a 5,        6-membered unsaturated heterocyclic ring;    -   R₄ is selected in the group consisting of: hydrogen, halogen,        hydroxy, cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl,        C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₄ is a        phenyl group, a 5-14 membered heterocyclic group; and any of        such phenyl or heterocyclic group is optionally substituted by        1, 2, 3 or 4 substituents selected from the group consisting of:        halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl and SF₅;    -   R₅ is selected in the group consisting of: hydrogen, halogen,        hydroxy, cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl,        C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₅ is a        phenyl group, a 5-14 membered heterocyclic group; and any of        such phenyl or heterocyclic group is optionally substituted by        1, 2, 3 or 4 substituents selected from the group consisting of:        halogen, cyano, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅;    -   R₆ is a moiety selected from the group consisting of:        isoxazolyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,        thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and such R₆ group        is optionally substituted by one or two substituents selected        from: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkanoyl;    -   R₇ is hydrogen or C₁₋₂alkyl;    -   R′ is H, C₁₋₄alkyl or C₁₋₄alkanoyl;    -   R″ is defined as R′;    -   R′ and R″ taken together with the interconnecting nitrogen atom        may form a 5-, 6-membered saturated or unsaturated heterocyclic        ring;        wherein at least one of R₄ and R₅ is hydrogen; and wherein only        one R₂ group ma be different from hydrogen.

Because of the presence of the fused cyclopropane, compounds of formula(I) are believed to have a “cis” disposition of the substituents (bothgroups linked to the bicyclic ring system are on the same face of thisbicyclic ring system).

In one embodiment of the present invention compounds of formula (I)′ areprovided which correspond to the compounds of formula (I), or saltsthereof, having “cis” disposition, represented by the bold highlight ofthe bonds

wherein G, A, p, n, R₁, R₂, and R₇ are defined as above for compounds offormula (I).

It will be appreciated that compounds of formula (I)′ possess at leasttwo chiral centres, namely at position 1 and 5 in the3-azabicyclo[3.1.0]hexane portion of the molecule. Because of the fixedcis disposition, the compounds may exist in two stereoisomers which areenantiomers with respect to the chiral centres in the cyclopropane. Itwill also be appreciated, in common with most biologically activemolecules that the level of biological activity may vary between theindividual stereoisomers of a given molecule. It is intended that thescope of the invention includes all individual stereoisomers(diastereoisomers and enantiomers) and all mixtures thereof, includingbut not limited to racemic mixtures, which demonstrate appropriatebiological activity with reference to the procedures described herein.

In compounds of formula (I)′ there are at least two chiral centres,which are located in the cyclopropane portion, as depicted below (thebold highlight of the bonds means the “cis” configuration); throughoptical resolution of a mixture containing the two stereoisomers whichare enantiomers with respect to the chiral centres in the cyclopropane,single steroisomers of compounds of formula (I)′ may be obtained asshown in the scheme below:

Absolute configuration of chiral center at position named 1 and 5 may beassigned using Cahn-Ingold-Prelog nomenclature based on groups'priorities.

In one embodiment of the present invention compounds of formula (IA) areprovided that correspond to stereochemical isomers of compounds offormula (I)′, enriched in configuration shown in the picture below atchiral centers at position named 1 and 5:

wherein G, A, p, n, R₁, R₂, and R₇ are defined as above for compounds offormula (I), or a salt thereof.

It is intended in the context of the present invention thatstereochemical isomers of formula (IA) enriched in one configuration atcenters named 1 and 5, correspond in one embodiment to at least 90% e.e.(enantiomeric excess). In another embodiment the isomers correspond toat least 95% e.e. In another embodiment the isomers correspond to atleast 99% e.e.

In another embodiment of the present invention compounds of formula (IH)are provided that correspond to stereochemical isomers of compounds offormula (I)′, enriched in configuration (1S,5R) or (1R,5R)

wherein G, A, p, n, R₁ and R₂ are defined as above for compounds offormula (I) and R₇ is hydrogen, or a salt thereof.

Different nomenclature for absolute configuration assigned to chiralcenter named 1 [(1R) or (1S)] may be generated by different meanings forG group.

For example, when the group G is a phenyl group, absolute configurationnomenclature for compounds of formula (IH) is (1S,5R).

It is intended in the context of the present invention thatstereochemical isomers enriched in configuration (1S,5R) or (1R,5R) offormula (IH) correspond in one embodiment to at least 90% e.e.(enantiomeric excess). In another embodiment the isomers correspond toat least 95% e.e. In another embodiment the isomers correspond to atleast 99% e.e.

In another embodiment of the present invention the stereochemicalisomers enriched in configuration (1R,5S) are provided.

In another embodiment of the present invention compounds of formula (IL)are provided that correspond to stereochemical isomers of compounds offormula (I)′, enriched in configuration shown in the picture below atchiral centers at position named 1 and 5:

wherein G, A, p, n, R₁, R₂ and R₇ are defined as above for compounds offormula (I), or a salt thereof.

The term ‘C₁₋₄alkyl’ as used herein as a group or a part of the grouprefers to a linear or branched alkyl group containing from 1 to 4 carbonatoms; examples of such groups include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tert butyl.

The term C₃₋₇ cycloalkyl group' as used herein means a non aromaticmonocyclic hydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; whileunsaturated cycloalkyls include cyclopentenyl and cyclohexenyl, and thelike.

The term ‘C₁₋₄ alkoxy group’ as used herein may be a linear or abranched chain alkoxy group, for example methoxy, ethoxy, propoxy,prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.

The term ‘C₁₋₄ alkanoyl group’ as used herein may be a linear or abranched chain alkanoyl group, for example acetyl, ethylcarbonyl,n-propylcarbonyl, i-propyl carbonyl, n-butylcarbonyl or t-butylcarbonyland the like.

The term ‘halogen’ as used herein refers to a fluorine, chlorine,bromine or iodine atom.

The term ‘halo C₁₋₄alkyl’ as used herein means an alkyl group having oneor more carbon atoms and wherein at least one hydrogen atom is replacedwith halogen such as for example a trifluoromethyl group and the like.

The term ‘halo C₁₋₄alkoxy group’ as used herein may be a C₁₋₄alkoxygroup as defined before substituted with at least one halogen,preferably fluorine, such as OCHF₂, or OCH₂F or OCF₃.

The term ‘aryl’ as used herein means an aromatic carbocyclic moiety suchas phenyl, biphenyl or naphthyl.

The term ‘5,6-membered monocyclic heteroaryl’ as used herein means anaromatic monocyclic heterocycle ring of 5 or 6 members and having atleast one heteroatom selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom.

Representative 5, 6 membered monocyclic heteroaryl groups include (butare not limited to): furyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl,isooxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl andtetrazolyl.

The term ‘8,11-membered bicyclic heteroaryl’ as used herein means anaromatic bicyclic heterocycle ring of 8 to 11 members and having atleast one heteroatom selected from nitrogen, oxygen and sulfur, andcontaining at least 1 carbon atom.

Representative 8, to 11 membered bicyclic heteroaryl groups include (butare not limited to): benzofuranyl, benzothiophenyl, indolyl, isoindolyl,azaindolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl,benzothiazolyl, quinazolinyl and phthalazinyl.

The term 5-14 membered heterocycle means a 5 to 7-membered monocyclic,or 7- to 14-membered polycyclic, heterocycle ring which is eithersaturated, unsaturated or aromatic, and which contains from 1 to 4heteroatoms independently selected from nitrogen, oxygen and sulfur, andwherein the nitrogen and sulfur heteroatoms may be optionally oxidized,and the nitrogen heteroatom may be optionally quaternized, includingbicyclic rings in which any of the above heterocycles are fused to abenzene ring as well as tricyclic (and higher) heterocyclic rings. Theheterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined above. Thus, in addition tothe aromatic heteroaryls listed above, heterocycles also include (butare not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like.

Any of these groups may be attached to the rest of the molecule at anysuitable position.

As used herein, the term “salt” refers to any salt of a compoundaccording to the present invention prepared from an inorganic or organicacid or base, quaternary ammonium salts and internally formed salts.Physiologically acceptable salts are particularly suitable for medicalapplications because of their greater aqueous solubility relative to theparent compounds. Such salts must clearly have a physiologicallyacceptable anion or cation. Suitably physiologically acceptable salts ofthe compounds of the present invention include acid addition saltsformed with inorganic acids such as hydrochloric, hydrobromic,hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, andwith organic acids, such as tartaric, acetic, trifluoroacetic, citric,malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic,maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic,isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic,anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic,alginic, galacturonic and arylsulfonic, for example benzenesulfonic andp-toluenesulfonic, acids; base addition salts formed with alkali metalsand alkaline earth metals and organic bases such asN,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine;and internally formed salts. Salts having a non-physiologicallyacceptable anion or cation are within the scope of the invention asuseful intermediates for the preparation of physiologically acceptablesalts and/or for use in non-therapeutic, for example, in vitro,situations.

In one embodiment, R₁ is halogen, cyano, acetyl, trifluoromethyl,trifluoromethoxy.

In one embodiment, R₂ is hydrogen. In another embodiment R₂ is C₁₋₄alkyl(e.g. methyl).

In one embodiment R₃ may be hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl, hydroxyl, phenyl or halogen.

In one embodiment R₄ may be hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl, halogen, phenyl or hydroxyl.

In one embodiment R₅ may be hydrogen, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl, phenyl, hydroxyl or halogen.

In one embodiment, R₆ is a group selected from: isoxazolyl,2-pyrrolidinonyl, —CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl,2-thienyl, 2-pyridyl, 2-thiazolyl which is optionally substituted by oneor two substituents selected from: halogen, cyano, C₁₋₂alkyl (e.g.methyl), haloC₁₋₂alkyl (e.g. trifluoromethyl), C₁₋₂alkoxy (e.g.methoxy), C₁₋₃alkanoyl (e.g. acetyl).

In one embodiment R₇ is hydrogen or methyl.

In another embodiment R₂ is hydrogen.

In one embodiment, p is 0, 1 or 2.

In another embodiment, p is 1.

In one embodiment, G is a phenyl group.

In another embodiment R₁ trifluoromethyl.

In one embodiment n is 3 or 4.

In one embodiment n is 4, 5 or 6. In another embodiment n is 4.

In another embodiment R₃ and R₄ are hydrogen, methyl, hydroxyl, phenylor fluorine.

In one embodiment R₃ may be hydrogen, an optionally substituted phenyl,methyl, a optionally substituted pyridyl, an optionally substitutedisooxazolyl or an optionally substituted thiazolyl.

In one embodiment, R₄ is hydrogen or methyl.

In another embodiment R₅ is hydrogen.

In another embodiment R₆ is isoxazolyl,2-pyrrolidinonyl,-1,1-dioxido-2-isothiazolidinyl.

In another embodiment R₇ is hydrogen.

In one embodiment, a compound of formula (IB) or a salt thereof isprovided, wherein R₁, R₂, R₃, R₄, R₅, p, n and R₇ are as defined forformula (I):

In Formula (IB), in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₃ and R₄ may be hydrogen, methyl,hydroxyl, phenyl or fluorine, R₅ is hydrogen and R₇ is hydrogen.

In Formula (IB), in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₄ may be hydrogen or methyl, R₃ may behydrogen, an optionally substituted phenyl, methyl, a optionallysubstituted pyridyl, an optionally substituted isooxazolyl or anoptionally substituted thiazolyl, R₅ is hydrogen and R₇ is hydrogen.

In Formula (IB), in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₄ may be hydrogen, methyl or phenyl,R₃ may be hydrogen, an optionally substituted phenyl, methyl, aoptionally substituted pyridyl, an optionally substituted isooxazolyl oran optionally substituted thiazolyl, R₅ is hydrogen and R₇ is hydrogen.

The absolute configuration of the compounds of the present invention wasmay be assigned in agreement with the method described in the PCTInternational Publication WO2005/080382.

Further embodiments of the present invention are compounds of formula(IB)′ which correspond to the stereochemical isomers of compounds offormula (IB) as defined above enriched in configuration (1 S,5R).

In one embodiment, a stereochemical isomer enriched in the (1S,5R)configuration of formula (IB)′ or a salt thereof is provided, whereinR₁, R₂, R₃, R₄, R₅, p, n and R₇ are as defined for formula (I):

In Formula (IB)′, in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₃ and R₄ may be hydrogen, methyl,hydroxyl, phenyl or fluorine, R₅ is hydrogen and R₇ is hydrogen.

In Formula (IB)′, in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₄ may be hydrogen or methyl, R₃ may behydrogen, an optionally substituted phenyl, methyl, a optionallysubstituted pyridyl, an optionally substituted isooxazolyl or anoptionally substituted thiazolyl, R₅ is hydrogen and R₇ is hydrogen.

In Formula (IB)′, in one embodiment, n is 4, p is 1, R₁ istrifluoromethyl, R₂ is hydrogen, R₄ may be hydrogen, methyl or phenyl,R₃ may be hydrogen, an optionally substituted phenyl, methyl, aoptionally substituted pyridyl, an optionally substituted isooxazolyl oran optionally substituted thiazolyl, R₅ is hydrogen and R₇ is hydrogen.

Certain of the compounds of the invention may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Pharmaceutical acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Solvates of the compound of the invention arewithin the scope of the invention. The compounds of formula (I) mayreadily be isolated in association with solvent molecules bycrystallisation or evaporation of an appropriate solvent to give thecorresponding solvates.

In addition, prodrugs are also included within the context of thisinvention. As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher,S. Ramon and H. Barbra “Improved oral drug delivery: solubilitylimitations overcome by the use of prodrugs”, Advanced Drug DeliveryReviews (1996) 19(2) 115-130, each of which are incorporated herein byreference.

Prodrugs are any covalently bonded carriers that release a compound ofstructure (I) in vivo when such prodrug is administered to a patient.Prodrugs are generally prepared by modifying functional groups in a waysuch that the modification is cleaved, either by routine manipulation orin vivo, yielding the parent compound. Prodrugs include, for example,compounds of this invention wherein hydroxy, amine or sulfhydryl groupsare bonded to any group that, when administered to a patient, cleaves toform the hydroxy, amine or sulfhydryl groups. Thus, representativeexamples of prodrugs include (but are not limited to) acetate, formateand benzoate derivatives of alcohol, sulfhydryl and amine functionalgroups of the compounds of structure (I). Further, in the case of acarboxylic acid (—COOH), esters may be employed, such as methyl esters,ethyl esters, and the like. Esters may be active in their own right andfor be hydrolysable under in vivo conditions in the human body. Suitablepharmaceutically acceptable in vivo hydrolysable ester groups includethose which break down readily in the human body to leave the parentacid or its salt.

Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention.

Hereinafter, compounds of formula (I) and their pharmaceuticallyacceptable salts, solvates and prodrugs defined in any aspect of theinvention (except intermediate compounds in chemical processes) arereferred to as “compounds of the invention”.

Those skilled in the art will appreciate that in the preparation of thecompounds of the invention, it may be necessary and/or desirable toprotect one or more sensitive groups in the molecule to preventundesirable side reactions. Suitable protecting groups for use accordingto the present invention are well known to those skilled in the art andmay be used in a conventional manner. See, for example, “Protectivegroups in organic synthesis” by T. W. Greene and P. G. M. Wuts (JohnWiley & sons 1991) or “Protecting Groups” by P. J. Kocienski (GeorgThieme Verlag 1994). Examples of suitable amino protecting groupsinclude acyl type protecting groups (e.g. formyl, trifluoroacetyl,acetyl), aromatic urethane type protecting groups (e.g.benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethaneprotecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl).Examples of suitable oxygen protecting groups may include for examplealky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl;alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such asacetate.

The present invention also includes isotopically-labelled compounds,which are identical to those recited in formula (I) and following, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention and pharmaceutically acceptable saltsthereof include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H,¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.

Compounds of the present invention and non-pharmaceutically acceptablesalts thereof that contain the aforementioned isotopes and/or otherisotopes of other atoms are within the scope of the present invention.Isotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distribution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I isotopes are particularly useful in SPECT (single photonemission computerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of the present invention andnon-pharmaceutically acceptable salts thereof can generally be preparedby carrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

Certain groups/substituents included in the present invention may bepresent as isomers. The present invention includes within its scope allsuch isomers, including racemates, enantiomers, tautomers and mixturesthereof. Certain of the substituted heteroaromatic groups included incompounds of formula (I) may exist in one or more tautomeric forms.

The present invention includes within its scope all such tautomericforms, including mixtures.

In one embodiment, example compounds of the invention include:

-   4-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-methyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-3,4-dihydro-2(1H)-pyrimidinone;    or a pharmaceutically acceptable salt thereof.

In another embodiment, example compounds of the invention include:

-   5-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-fluorophenyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(3,5-dimethyl-4-isoxazolyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(6-methyl-2-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   5-methyl-4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-methyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-3,4-dihydro-2(1H)-pyrimidinone;-   4-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the compounds of formula (I) are selected fromthe group consisting of hydrochloride salts, of the compounds listedbelow:

-   5-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-fluorophenyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(3,5-dimethyl-4-isoxazolyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-(6-methyl-2-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   5-methyl-4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;-   4-methyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-3,4-dihydro-2(1H)-pyrimidinone;-   4-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone.

Some of the compounds of the present invention may be prepared followingsome of the procedures described in PCT International PublicationWO2005/080382.

The present invention also provides a process for preparing a compoundof formula (I)′ or a salt thereof as defined above, which comprises thesteps of:

a) reacting a compound of formula (II):

wherein R₁, R₇ and p are as defined for formula (I), with a compound offormula (III):

wherein R₂, A and n are as defined for formula (I) and X is a leavinggroup,

Or

b) reacting a compound of formula (II) as above defined:

with a compound of formula (IV)

wherein R₂, A and n are as defined for formula (I);and thereafter optionally for process (a) or process (b):(i) removing any protecting group(s); and/or(ii) forming a salt; and/or(iii) converting a compound of formula (I)′ or a salt thereof to anothercompound of formula (I)′ or a salt thereof.

Process (a) may be performed using conventional methods for theformation of a tertiary amine. The leaving group X can be halogen suchas chlorine. Alternatively X can be a sulfonyloxy group such C₁₋₂alkylsulfonyloxy (e.g. methanesulfonyloxy), C₁₋₄alkylsulfonyloxy orhaloC₁₋₄alkylsulfonyloxy (e.g. trifluoromethanesulfonyloxy); orarylsulfonyloxy wherein aryl is optionally substituted phenyl, anoptionally substituted 5- or 6-membered heteroaromatic group, or anoptionally substituted bicyclic group, for example optionallysubstituted phenyl, wherein in each case the optional substituents areone or more C₁₋₂alkyl groups; e.g. para-toluenesulfonyloxy. When X is ahalogen the reaction may be carried out using a base such as potassiumcarbonate in the presence of a source of iodide such as sodium iodide ina solvent such as N,N-dimethylformamide at a suitable temperature, e.g.60° C.

Process (b) may be performed using conventional methods for theformation of a tertiary amine by means of reductive ammination. Forexample when, for compounds of formula (IV) R₂ is hydrogen, the reactionmay be carried out using sodium triacetoxy borohydride in a suitablesolvent such as 1,2 dichloroethane at 0° C.

In another embodiment the present invention provides a process for thepreparation of compounds of formula (Ia), i.e. a compound of formula(I)′ wherein p is 1 or 2 and one R₁ is a group R₆, comprises thefollowing steps:

c) reacting a compound of formula (V):

wherein R₁, and R₇ are as defined for formula (I), Pg is a suitableamine protecting group such as for example tert-buthoxy carbonyl group,p is 0 or 1 and Y is halogen, a perfluoroalkylsulfonyloxy group (e.g.trifluoromethylsulfonyloxy), or Y is a group M selected from a boronderivative (e.g. a boronic acid function B(OH)₂) or a metal functionsuch as trialkylstannyl (e.g. SnBu₃), zinc halide or magnesium halide;with a compound of formula R₆—Y₁, wherein R₆ is an optionallysubstituted isoxazolyl, thienyl, thiazolyl or pyridyl, group, Y₁ ishalogen when Y is a group M; or, when Y is halogen or aperfluoroalkylsulfonyloxy group, Y₁ is a group M as defined above orhydrogen that can be activated by a suitable base (e.g. Cs₂CO₃) in thepresence of a suitable transition metal (e.g. Pd); “leaving group” is asunderstood by a skilled chemist, i.e. a group which can be displaced bya nucleophile in e.g. a S_(N)2, S_(N)1 or S_(N)Ar type reaction; to forma compound of formula (XXXIV)

wherein R₁, and R₇ are as defined for formula (I), Pg is a suitableamine protecting group such as for example tert-buthoxy carbonyl group,p is 0 or 1 and R₆ is an optionally substituted isoxazolyl, thienyl,thiazolyl or pyridyl, group;d) removing the Pg group;e) reacting the obtained product with a compound of formula (III) or(IV), as above defined, under the conditions described for processes a)or b);and thereafter optionally:(i) removing any protecting group(s); and/or(ii) forming a salt; and/or(iii) converting a compound of formula (Ia) or a salt thereof to anothercompound of formula (Ia) or a salt thereof.

Reaction of a compound of formula (V) with R₁—Y₁ according to process(c) may be effected in the presence of a transition metal e.g.,palladium catalyst such as bis-triphenylphosphinepalladium dichloride,tetrakis-triphenylphosphinepalladium (0) or the complex formed in situfrom tris(dibenzylideneacetone) dipalladium(0) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. When M is a boronicacid function such as B(OH)₂ the reaction may be carried out under basicconditions, for example using aqueous sodium carbonate in a suitablesolvent such as dioxane. When M is trialkylstannyl the reaction may becarried out in an inert solvent, such as xylene or dioxane optionally inthe presence of LiCl. When M is a zinc or magnesium halide the reactionmay be effected in an aprotic solvent such as tetrahydrofuran. When M ishydrogen that can be activated by a suitable base (e.g. Cs₂CO₃) in thepresence of a suitable transition metal (e.g. Pd) the reaction may becarried out in an inert solvent such as dioxane in the presence of asuitable base such as Cs₂CO₃. The substituent Y may be halogen such asbromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxy; andY₁ is may be a group M, such as hydrogen that can be activated by asuitable base (e.g. Cs₂CO₃) in the presence of a suitable transitionmetal (e.g. Pd).

Compounds of formula (II) may be prepared by methods well known in theart (e.g. J. Med. Chem. 1981, 24, 481-490 or PCT InternationalPublication WO2005/080382). Interconversion of groups R₁ may be affectedby methodology well known in the art (e.g. demethylation of a methoxygroup resulting in a hydroxy group using a suitable Lewis acidic reagentsuch as boron tribromide in an inert solvent such as dichloromethane).

In one aspect of the present invention there is provided a process forthe preparation of compounds of formula (IIa), i.e. a compound ofgeneral formula (II) wherein R₇ is hydrogen and G is a phenyl ring andR₁ is defined as for compounds of formula (I).

The process may be conveniently performed also for preparing compoundsof formula (IIb), wherein the phenyl moiety of compound (IIa) isreplaced by pyridine. This process comprises the following steps:

wherein:step (a′) means diazotation of an aniline (VI) followed by reaction withmaleimide to give 3-arylmaleimide (VII);step (b′) means cycloropanation of (VII) to provide bicyclic imide(VIII);step (c′) means reduction of imide (VIII) to give compounds of formula(IIIa).

Step (a′) may be effected using conventional methods for the Meerweinreaction (e.g. J. Am. Chem. Soc. 1955, 77, 2313 describes the formationof arylmaleimides using this approach). Alternatively, in many casesthis step is suitably performed applying a procedure where to a mixtureof maleimide, an appropriate copper (II) salt such as anhydrous CuCl₂,and a suitable organonitrite, such as tert-butyl nitrite, in acompatible solvent, such as acetonitrile, is slowly added a solution ofa compound of formula (VI). This is followed by allowing time to reactas appropriate and a suitable workup.

Step (b′) consists of slow addition of a solution of purified compoundof formula (VII), or mixtures containing a compound of formula (VII),dissolved in a suitable solvent such as dimethylsulfoxide, to a solutionof trimethylsulfoxonium iodide in a suitable solvent such asdimethylsulfoxide and a suitable base, such as sodium hydride. This isfollowed by allowing time to react as appropriate and a suitable workup.

Step (c′) can be performed using a suitable reducing agent in acompatible solvent, such as borane in tetrahydrofuran or Red-Al® intoluene at an appropriate temperature, such as for example 65° C. in thecase of borane as the reducing agent. This is followed by a suitableworkup.

In another aspect of the present invention an alternative syntheticprocess for the preparation of compounds of formula (II), is provided.This process comprises the following steps:

wherein:R₁, p and G are as defined for formula (I), R₈O is a suitable alkoxygroup, PG is an appropriate protecting group and Y may be halogen suchas bromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxyand comprising the following steps:step (a″) means coupling reaction of a(2,5-dihydro-1H-pyrrol-3-yl)boronate (IX) with the aromatic halogen orsulfonyloxy derivative (X);step (b″) means cycloropanation of (XI) followed by, if appropriate,deprotection to provide bicyclic amine (II).

Step (a″) may be effected using conventional methods for the Suzukicoupling, e.g. using tetrakis(triphenylphosphine)palladium(0) as thesource of catalytic palladium(0) in the presence of cesium fluoride inan appropriate solvent such as tetrahydrofuran at a suitabletemperature. (R₈O)₂B may suitably be4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and PG benzyl, representinga compound of structure (X) as reported in Synlett 2002, 5, 829-831.

Step (b″) consists of a cyclopropanation reaction effected for exampleusing the reagent generated from trimethylsulfoxonium iodide and asuitable base such as sodium hydride. This is followed by a deprotectionreaction.

In another aspect of the present invention there is provided a syntheticprocess for the preparation of compounds of formula (IIc), i.e.compounds of general formula (II) wherein R₇ is C₁₋₂ alkyl and G is aphenyl group. This process comprises the following steps:

wherein:step (a″) means bromuration of compound (XV) to give compound (XVI);step (b″) means reaction of compound (XVI) with a benzylic amine with abenzylic amine (susceptible to afford benzylic cleavage in acidicconditions) to give imide (XVII);step (c″) means coupling of compound (XVII) with an aryl boronic acid togive compound (XVIII);step (d″) means removal of the benzylic protecting group of compound(XVIII) to give compound (XIX);step (e″) means cycloropanation of (XIX) to provide bicyclic imide (XX);step (f″) means reduction of imide (XX) to give compounds of formula(IIc).

Step (a′) may be effected using bromine in the presence of AlCl3, andheating the mixture at high temperature, suitably 120° C.

Step (b″) may be performed heating compound (XVI) together with anappropriate benzylic amine (suitably as 3,4-(dimethoxy)benzylamine or2,4-(dimethoxy)benzylamine) in the presence of AcONa and AcOH.

Step (c″) may be effected using conventional methods for the Suzukicoupling, e.g. using Pd(PPh₃)₂Cl₂ as the source of catalyticpalladium(0) in the presence of cesium fluoride, BnEt₃NCl and a genericarylboronic acid in an appropriate mixture of solvents, (such astoluene/H₂O 1:1) at a suitable temperature (such as 90° C.).

Step (d″) may be performed through an appropriate method for acidiccleavage of benzylic protecting group, such as one of those reported in“Protective groups in organic synthesis” by T. W. Greene and P. G. M.Wuts (John Wiley & sons 1991) or “Protecting Groups” by P. J. Kocienski(Georg Thieme Verlag 1994). Suitably, if the benzylic group isrepresented by 3,4-(dimethoxy)benzyl, protection may be removed throughreaction of compound (XVIII) with TFA and anisole in the presence ofsulforic acid.

Step (e″) consists of slow addition of a solution of purified compoundof formula (XIX), or mixtures containing a compound of formula (XIX),dissolved in a suitable solvent such as dimethylsulfoxide, to a solutionof trimethylsulfoxonium iodide in a suitable solvent such asdimethylsulfoxide and a suitable base, such as sodium hydride. This isfollowed by allowing time to react as appropriate and a suitable workup.

Step (f″) can be performed using a suitable reducing agent in acompatible solvent, such as borane in tetrahydrofuran or Red-Al® intoluene at an appropriate temperature, such as for example 65° C. in thecase of borane as the reducing agent. This is followed by a suitableworkup.

A compound of formula (III), as above defined, may itself be prepared byreacting a compound of formula (XXI):

wherein R₃, R₄ and R₅ are as defined as for formula (I), with a compoundof formula (XIII):

L(CHR₂)nX  (XIII)

wherein R₂ is defined as for formula (I), X is as above defined and L isa leaving group.

The leaving group L can be halogen, such as chlorine. Alternatively Lcan be a sulfonyloxy group such C₁₋₄alkylsulfonyloxy (e.g.methanesulfonyloxy), C₁₋₄alkylsulfonyloxy or haloC₁₋₄alkylsulfonyloxy(e.g. trifluoromethanesulfonyloxy); or arylsulfonyloxy wherein aryl isoptionally substituted phenyl, an optionally substituted 5- or6-membered heteroaromatic group, or an optionally substituted bicyclicgroup, for example optionally substituted phenyl, wherein in each casethe optional substituents are one or more C₁₋₂alkyl groups; e.g.para-toluenesulfonyloxy. When L is a halogen the reaction may be carriedout using a base such as potassium carbonate in the presence of a sourceof iodide such as sodium iodide in a solvent such asN,N-dimethylformamide at a suitable temperature, e.g. 60° C.

A compound of formula (IV), as above defined, may itself be preparedthrough the following steps:

f) reacting a compound of formula (XXI):

wherein R₃, R₄ and R₅ are as defined as for formula (I), with a compoundof formula (XXII)

MCR₂(CHR₂)_(n-1)X  (XXII)

wherein R₂ is defined as for formula (I), X is as above defined and M isan appropriate carbonylic protecting group (for example dimethylacetaleor dioxalane);and theng) cleavage of the protecting group.

Cleavage of the protecting group may be carried out under appropriateconditions known to the man skilled in the art. For example, when M isdimethylacetale, the cleavage may carried out by treatment with adiluted solution of hydrochloric acid in dioxane or methanol undergentle heating (e.g. 60° C.).

A compound of formula (IV), as above defined, may be prepared throughthe following steps:

h) reacting a compound of formula (XXI), as above defined:

with a compound of formula (XXIII)

NCR₂(CHR₂)_(n-1)X  (XXIII)

wherein R₂ is defined as for formula (I), X is as above defined and N isa protected alcoholic function (for example: terbutyldimethylsilyl);and theni) cleavage of the protecting group under appropriate conditions knownto the man skilled in the art and subsequent oxidation of the freealcoholic function obtained to carbonyl group.

For example when N is a terbutyl dimethyl silyl protecting group thecleavage can be performed by treatment with a 1N solution ofhydrochloric acid in dioxane at 0° C. for 1 hour. Appropriate conditionsfor the oxidation step comprise Dess-Martin periodinane mediatedoxidation in dry THF as solvent at 0° C. for 1 hour.

Compounds of formula (XIII), (XXII) and (XXIII) are commerciallyavailable or may be prepared through reactions known in the literature.

Compounds of formula (XXI) are either commercially available or may beprepared through reactions known in the literature or through theprocedures herebelow described.

A suitable synthetic process for the preparation of compounds (XXI),wherein R₃, R₅ and R₅ are as defined as for formula (I), comprises thefollowing steps:

m)

followed by step n):

followed by step o):

followed by step p):

and then by step q):

Step m) means sulfur methylation and may be performed starting fromcompounds of formula (XXIV), wherein R₃ and R₄ are as defined as forformula (I), using MeI in refluxing ethanol as solvent;

Step n) means conversion of the carbonyl group in compounds of formula(XXV), wherein R₃ and R₄ are as defined as for formula (I), into ahalogen atom and may be performed for example by using POCl3 in dioxaneat reflux;Step (0) means palladium catalyzed coupling of compounds of formula(XXVI), wherein wherein R₃ and R₄ are as defined as for formula (I) andX is alogen, i.e chlorine or iodine, with the suitable aryl orheteroaryl boronic acids. Step (o) may be performed using conventionalmethod for the Suzuky coupling, using for example Pd(OAc)₂ as the sourceof catalytic palladium (0), in the presence of Na₂CO₃ as base and asuitable aryl boronic acid or aryl boronic ester in an appropriatesolvent, such as nPrOH;Step p) means oxidation of compounds of formula (XXVII), wherein R₃, R₄and R₅ are as defined as for formula (I), by means of appropriateoxidative agents such as for example oxone in a suitable solvent i.e.MeOH;Step q) means basic hydrolysis of the methyl sulphonyl group ofcompounds of formula (XXVIII), wherein R₃, R₄ and R₅ are as defined asfor formula (I), using for example a diluted solution of NaOH at roomtemperature in dioxane as solvent;

Compounds of formula (XXIV) are either commercially available or may beprepared through reactions known in the literature.

Interconversion reactions between compounds of formula (I)′ and saltsthereof may be performed using methods well known in the art. Examplesinclude:

(i) converting one or more of R₁ from alkoxy (e.g. methoxy) to hydroxy,(ii) converting one or more of R₁ from hydroxy to sulfonyloxy, such asalkylsulfonyloxy or haloalkylsulfonyloxy, e.g. methanesulfonyloxy oralkylsulfonyloxy or trifluoro-methanesulfonyloxy,(iii) converting one or more of R₁ from halogen orperfluoroalkylsulfonyloxy to cyano; and optionally thereafter forming asalt of formula (I)′.

When a specific enantiomer or diastereoisomer of a compound of formula(I) or salts thereof, is required, this may be obtained for example byresolution of a corresponding enantiomeric or diastereosiomeric mixtureusing conventional methods.

Thus, for example, specific enantiomers or diastereoisomers of thecompounds may be obtained from the corresponding enantiomeric ordiastereoisomeric mixture using chiral chromatographic methods such asfor example chiral HPLC.

Alternatively a specific enantiomer or diastereoisomer of a compound ofgeneral formula (I), or salts thereof, may be synthesised from theappropriate optically active intermediates using any of the generalprocesses described herein.

Compounds of formula (I) or pharmaceutically acceptable salts thereof,have been found to exhibit affinity for dopamine receptors, inparticular the D₃ receptor, and are expected to be useful in thetreatment of disease states which require modulation of such receptors,such as psychotic conditions.

Many of the compounds of formula (I) or pharmaceutically acceptablesalts thereof have also been found to have greater affinity for dopamineD₃ than for D₂ receptors. The therapeutic effect of currently availableantipsychotic agents (neuroleptics) is generally believed to be exertedvia blockade of D₂ receptors; however this mechanism is also thought tobe responsible for undesirable extrapyramidal side effects (eps)associated with many neuroleptic agents. It has been suggested thatblockade of the recently characterised dopamine D₃ receptor may giverise to beneficial antipsychotic activity without significant eps. (seefor example Sokoloff et al, Nature, 1990; 347: 146-151; and Schwartz etal, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). In oneembodiment compounds of formula (I) or salts thereof are provided whichhave higher (e.g. ≧10× or ≧100× higher) affinity for dopamine D₃ thandopamine D₂ receptors (such affinity can be measured using standardmethodology—see herein).

Compounds of the invention may suitably be used as selective modulatorsof D₃ receptors.

From the localisation of D₃ receptors, it could also be envisaged thatthe compounds could also have utility for the treatment of substanceabuse where it has been suggested that D₃ receptors are involved (e.g.see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of suchsubstance abuse include alcohol, cocaine, heroin and nicotine abuse.Other conditions which may be treated by the compounds include substancerelated disorders, dyskinetic disorders such as Parkinson's disease,neuroleptic-induced parkinsonism and tardive dyskinesias; depression;anxiety, cognitive impairment including memory disorders such asAlzheimers disease, sexual dysfunction, sleep disorders, emesis,amnesia, aggression, vertigo, dementia, circadian rhythm disorders andgastric motility disorders e.g. IBS.

A wide range of psychiatric and neuropsychiatric disorders appear to berelated to Obsessive-Compulsive Disorder, and form a family of relateddisorders referred to as obsessive-compulsive (OC) spectrum disorders.The compounds of the invention may be used for the treatment of anobsessive-compulsive spectrum disorder, including somatoform disorderssuch as body dysmorphic disorder and hyperchondriasis, bulimia nervosa,anorexia nervosa, binge eating, paraphilia and nonparaphilic sexualaddictions, Sydeham's chorea, torticollis, autism, compulsive hoarding,and movement disorders, including Tourette's syndrome. As used herein,the phrase “obsessive-compulsive spectrum disorder” is intended toinclude Obsessive-Compulsive Disorder.

The compounds of the invention are also useful for the treatment ofpremature ejaculation.

The terms describing the indications used herein are classified in theDiagnostic and Statistical Manual of Mental Disorders, 4th Edition,published by the American Psychiatric Association (DSM-IV) and/or theInternational Classification of Diseases, 10th Edition (ICD-10). Thevarious subtypes of the disorders mentioned herein are contemplated aspart of the present invention. Numbers in brackets after the listeddiseases below refer to the classification code in DSM-IV.

The term “psychotic disorder” includes:

Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).

The term “substance-related disorder” includes:

Substance-related disorders including Substance Use Disorders such asSubstance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide.

Compounds of the invention may be useful for the treatment of cognitionimpairment.

The term “cognition impairment” includes cognition impairment in otherdiseases such as schizophrenia, bipolar disorder, depression, otherpsychiatric disorders and psychotic conditions associated with cognitiveimpairment, e.g. Alzheimer's disease.

In a further aspect therefore the present invention provides a method oftreating a condition for which modulation of dopamine receptors(especially dopamine D₃ receptors) is beneficial, which comprisesadministering to a mammal (e.g. human) in need thereof an effectiveamount of a compound of the invention.

Modulation, as used herein, especially refers to inhibition/antagonism(which may also translate into inverse agonism in constitutively activereceptor systems).

In one embodiment, the condition is a substance-related disorder, apsychotic disorder, an obsessive compulsive spectrum disorder orpremature ejaculation.

The invention also provides a compound of the invention for use intherapy.

The invention also provides a compound of the invention for use in thetreatment of a condition in a mammal for which modulation of dopaminereceptors (especially dopamine D₃ receptors) is beneficial.

The invention also provides the use of a compound of the invention inthe manufacture of a medicament for the treatment of a condition in amammal for which modulation of dopamine receptors (especially dopamineD₃ receptors) is beneficial.

In one embodiment, compounds of the invention are used in the treatmentof psychoses such as schizophrenia, in the treatment of substance abuse,in the treatment of obsessive compulsive spectrum disorders, in thetreatment of premature ejaculation.

Also provided is the use of a compound of the invention in themanufacture of a medicament for the treatment of a psychotic condition,substance abuse in a mammal, obsessive compulsive spectrum disorders,and premature ejaculation.

Also provided is a compound of the invention for use in the treatment ofa psychotic condition (e.g. schizophrenia), substance abuse, obsessivecompulsive spectrum disorders, and premature ejaculation in a mammal.

Also provided is a compound of the invention or for use as an activetherapeutic substance in a mammal, e.g. for use in the treatment of anyof the conditions described herein.

“Treatment” includes prophylaxis, where this is appropriate for therelevant condition(s).

For use in medicine, the compounds of the present invention are usuallyadministered as a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect a pharmaceuticalcomposition comprising a compound of the invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe for use in the treatment of any of the conditions described herein.

Compound of the invention may be administered by any convenient method,for example by oral, parenteral (e.g. intravenous), buccal, sublingual,nasal, rectal or transdermal administration and the pharmaceuticalcompositions adapted accordingly.

Compound of the invention which are active when given orally can beformulated as liquids or solids, for example syrups, suspensions oremulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example an aqueous solvent such as water, ethanol orglycerine, or a non-aqueous solvent, such as polyethylene glycol or anoil. The formulation may also contain a suspending agent, preservative,flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluoro-chlorohydrocarbon. The aerosoldosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

In one embodiment, the composition is in unit dose form such as atablet, capsule or ampoule.

Each dosage unit for oral administration contains for example from 1 to250 mg (and for parenteral administration contains for example from 0.1to 25 mg) of a compound of the invention calculated as the free base.

The compounds of the invention will normally be administered in a dailydosage regimen (for an adult patient) of, for example, an oral dose ofbetween 1 mg and 500 mg, for example between 10 mg and 400 mg, e.g.between 10 and 250 mg or an intravenous, subcutaneous, or intramusculardose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg,e.g. between 1 and 25 mg of the compound of the formula (I) or apharmaceutically acceptable salt thereof calculated as the free base,the compound being administered 1 to 4 times per day. Suitably thecompounds will be administered for a period of continuous therapy, forexample for a week or more.

Biological Test Methods

Functional potency of compounds of this invention can be measured by thefollowing GTPS scintillation proximity assay (GTPS-SPA). Cells used inthe study are Chinese Hamster Ovary (CHO) Cells.

Cell Line CHO_D2 CHO_D3

Dopamine CHO D₃ (Biocat no 1060) transduced with bacmam G0 G-protein(Biocat no 97886)

All steps are performed at 4° C. Cell membranes are prepared as follows.Cell pellets are resuspended in 10 volumes of 50 mM HEPES, 1 mM EDTA pH7.4, using KOH. Cells are homogenised within a glass waring blender for2 bursts of 15 secs in 200 mls of buffer (50 mM HEPES, 1 mM leupeptin,25 μg/ml bacitracin, 1 mM EDTA, 1 mM PMSF, 2 μM Pepstatin A). (thelatter 2 reagents added as fresh ×100 and ×500 stocks respectively inethanol). The blender is plunged into ice for 5 mins after the firstburst and 10-40 mins after the final burst to allow foam to dissipate.The material is then spun at 500 g for 20 mins and the supernatant spunfor 36 mins at 48,000 g. The pellet is resuspended in the same buffer asabove but without PMSF and Pepstatin A. The material is then forcedthrough a 0.6 mm needle, made up to the required volume, (usually ×4 thevolume of the original cell pellet), aliquoted and stored frozen at −80°C.

The final top concentration of test drug is 3 μM in the assay and 11points serial dilution curves 1:4 in 100% DMSO are carried out using aBiomek FX. The test drug at 1% (0.5 ul) total assay volume (TAV) isadded to a solid, white Greiner polypropylene 384-well assay plate. 50%TAV (250) of precoupled (for 60 mins at RT) membranes, 5 μg/well, andWheatgerm Agglutinin Polystyrene Scintillation Proximity Assay beads(RPNQ0260, Amersham), 0.25 mg/well, in 20 mM HEPES (pH 7.4, 100 mM NaCl,10 mM MgCl2), 60 μg/mL saponin and 30 uM GDP is added. The thirdaddition is a 20% TAV (10 ul) addition of either buffer, (agonistformat) or EC80 final assay concentration of agonist, Quinelorane,prepared in assay buffer (antagonist format). The assay is started bythe addition of 29% TAV (15 ul) of GTP[35S] 0.38 nM final (37 MBq/mL,1160 Ci/mmol, Amersham). After all additions assay plates are spun downfor 1 min at 1,000 rpm. The final assay cocktail (45.5 μl) is incubatedat room temperature to equilibrate for 3-6 hours before reading on aViewLux™ (613/55 filter) luminescence imager 5 min/plate.

The effect of the test drug over the basal generates fpKi values of testdrug are calculated from the IC₅₀ generated by “antagonist format”experiment, using Cheng & Prusoff equation: fKi=IC50/1+([A]/EC50) where:[A] is the concentration of the agonist Quinelorane in the assay andEC50 is the Quinelorane EC50 value obtained in the same experiment. fpKiis defined as −logfKi.

pKi results are only estimated to be accurate to about 0.3-0.5.

In the context of the present invention functional pKi (fpKi,corresponding to the negative logarithm of fKi) is used instead offunctional Ki (fKi) and the compounds of formula (I) and salts thereoftypically show fpKi for D3 receptors comprised between approximately 7.0and 8.5.

Here below a list of examples is provided which showed no activity inthe D2 GTPS-SPA assay up to the highest concentration tested in theassay (3 μM) and thus considered to be selective for D3 over D2receptors:

E3, E4, E5, E6, E7, E8, E9, E11, E12. EXAMPLES

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without any further purification.

In the procedures that follow, after each starting material, referenceto a Preparation or Example by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

Where reference is made to the use of a “similar” procedure, as will beappreciated by those skilled in the art, such a procedure may involveminor variation, for example reaction temperature, reagent/solventamount, reaction time, work-up conditions or chromatographicpurification conditions.

Compounds may be named using ACD/Name PRO6.02 chemical naming software(Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada)or ISIS/Draw 2.5 SR 2 Autonom (MDL Information System, Inc)

All temperatures refer to ° C. (degrees Centigrade).

Proton Magnetic Resonance (NMR) spectra may be typically recorded eitheron Varian instruments at 300, 400 or 500 MHz, or on a Bruker instrumentat 300 and 400 MHz. Chemical shifts are expressed in parts of million(ppm, δ units). Coupling constants are in units of hertz (Hz) chemicalshifts are reported in ppm downfield (d) from Me₄Si, used as internalstandard, and are assigned as singlets (s), broad singlets (bs),doublets (d), doublets of doublets (dd), triplets (t), quartets (q) ormultiplets (m).

Mass spectra (MS) are typically taken on a 4 II triple quadrupole MassSpectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer,operating in ES (+) and ES (−) ionization mode or on an Agilent LC/MSD1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization modecoupled with HPLC instrument Agilent 1100 Series. In the mass spectraonly one peak in the molecular ion cluster is reported.

LCMS may be typically recorded under the following conditions:

DAD chromatographic traces, mass chromatograms and mass spectrums aretypically taken on a HPLC/MS Acquity™ system coupled with a MicromassZQ™ mass spectrometer operating in ESI positive. The phases used are: A)H2O/ACN 95/5+0.1% TFA; B) H2O/ACN 5/95+0.1% TFA. The gradient is: t=0min) 95% A 5% B, t=0.25) 95% A 5% B, t=3.30) 100% B, t=4.0) 100% B,followed by 1 min of reconditioningColumn: Acquity BEH C18 2.1×50 mm 1.7 um 35° C. Flow: 600 uL/min.Mass tune: Capillary 3.25 kV, cone 20V, source temperature 115° C.desolvation T 350° C.

Preparative LC-MS purifications may be typically performed under thefollowing conditions: Instrument: HPLC-MS preparative system Waters(2767 and 2525) coupled with photodiode array detector and Micromass ZQ.Column: Waters XTerra MS C18 (19×300 mm, 10 um). Flow rate 20 ml/min.Mobile phase: A phase=water+0.1% TFA, B phase=acetonitrile+0.1% TFA.0-3.0 min (A: 90%, B: 10%), 3.0 min (A: 90%, B: 10%), 3.0-26.0 min (A:5%, B: 95%), 26.0 min (A: 5%, B: 95%), 26.0-30.0 min (A: 5%, B: 95%),30.0 min (A: 5%, B: 95%), 30.0-30.5 min (A: 90%, B: 10%), 30.5 min (A:90%, B: 10%), 30.5-31.5 min (A: 90%, B: 10%). The fractions containingthe pure material may be collected and the solvents evaporated. The soobtained trifluoroacetate salts may be neutralized by passing over SCXcartridge.

Preparative HPLC purifications may be typically performed under thefollowing conditions:

Instrument: Shimadzu (LC/8A and SCL/10A) coupled with UVspectrophotometric dector (SPD/6A). Column: Waters SymmetryPrep C1819×30 mm×7 um; flow rate: 20 ml/min; mobile phase: Aphase=water/acetonitrile 9/1+0.5% TFA, B phase=water/acetonitrile5/95+0.5% TFA using a 30 min gradient of 5-100% solvent B.

The fractions containing the pure material may be collected and thesolvents evaporated.

The so obtained trifluoroacetate salts may be neutralized by passingover SCX cartridge.

For reactions involving microwave irradiation, a Personal ChemistryEmrys™ Optimizer may be used.

Flash silica gel chromatography may be carried out on silica gel 230-400mesh (supplied by Merck AG Darmstadt, Germany) or over Varian Mega Be—Sipre-packed cartridges or over pre-packed Biotage silica cartridges.

In a number of preparations, purification may be performed using eitherBiotage manual flash chromatography (Flash+) or automatic flashchromatography (Horizon) systems. All these instruments work withBiotage Silica cartridges.

Optical rotations may be measured using a (Perkin Elmer Model 341)polarimeter operating at 589 nm (Sodium source). Measurements may bemade using a 1 decimeter microcell thermostated at 23° C. Concentrationsmay be typically 10 mg/ml (c=1).

Melting point determination may be performed on a Buchi B-540 apparatus.

Column chromathography may be carried out over silica gel (Merck AGDarmstaadt, Germany).

The following abbreviations are used in the text: n-PrOH=n-propanol,Pd(Oac)₂, MeOH=Methanol, DCM=dichloromethane, DMSO=dimethyl sulfoxide;DMF=N,N′-dimethylformamide; THF=tetrahydrofuran,Pd(dba)₂=palladiumdibenzylideneacetone, DIPEA=diisopropylethylemine;DME=dimethoxyethane, TEA=triethylamine; DCE=dichloroethane, Tlc refersto thin layer chromatography on silica plates, and dried refers to asolution dried over anhydrous sodium sulphate, r.t. (RT) refers to roomtemperature, Rt=retention time, SPE Cartridge=Solid Phase ExtractionCartridge; SCX Cartridge=Strong Cation Exchange Cartridge,PS-isocyanate=polimer supported isocyanate resin.

Preparation 1: 3-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione(Prep1)

A mixture of hydrochloric acid (37% in water, 285 mL) and water (190 mL)was added to 4-(trifluoromethyl)aniline (150 g, 116 mL) at roomtemperature with vigorous stirring and the formed precipitate wasallowed to stir for further 30 minutes. Temperature was reduced to 0° C.and sodium nitrite (70.6 g) in 180 mL of water was added dropwise to thestirred suspension. At the end of diazotisation, a clear yellow solutionwas obtained. Maleimide (180 g) in acetone (1.1 L) was added dropwise at0° C. and then the pH of the solution was adjusted to 3-3.5 by addingsodium acetate. Copper (II) chloride (18.8 g) was added to thevigorously stirred mixture. After a few minutes a gas started to develop(conspicuous foaming). The reaction mixture was allowed to stir at 0° C.for 1 h and overnight at room temperature. Acetone was removed in vacuo,the residue was filtered and dried overnight in vacuo to give the titlecompound (155 g) as a light brown solid.

MS (m/z): 242.2 [MH]⁺.

Preparation 2:(1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]-hexane-2,4-dione(Prep2)

Milled sodium hydroxide (40 g) was added in small portions to a stirredsolution of trimethylsulfoxonium iodide (219 g) in DMSO (anhydrous, 2L).The resulting mixture was allowed to stir at room temperature for 1.5 h.3-[4-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (Prep1, 120 g)dissolved in DMSO (anhydrous, 0.5 L) was then added dropwise and theresulting mixture was allowed to stir at room temperature for 20minutes. Temperature was then reduced to 0° C. and aqueous saturatedNH₄Cl (2 L) was slowly added, followed by Et₂O (1 L). After separationof the two phases, the aqueous layer was repeatedly extracted with Et₂O(3×1 L). Combined organic layers were washed with brine (2×1 L) and thendried over Na₂SO₄. Evaporation of the solvent gave a light brown solidwhich was suspended in 1 L of dichloromethane and 1 L of cyclohexane.The mixture was allowed to stir at room temperature for 45 minutes andthen filtered to give the title compound (116 g) as white solid.

MS (m/z): 256.1 [MH]⁺.

Preparation 3:(1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]-hexane(Prep3)

Borane (1M in tetrahydrofuran, 1.4 l) was charged into a 5 l reactorunder N₂ and cooled at 0° C.(1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione(Prep2, 101 g) dissolved in anhydrous THF (1 L) was then added dropwisewith vigorous stirring whereby the temperature was constantly kept below5° C. and gas evolution was monitored. At the end of the addition theresulting mixture was allowed to stir at 0° C. for 1 h and then at roomtemperature overnight. The mixture was then cooled to 0° C. and methanol(200 mL) followed aqueous 6M hydrochloric acid solution (0.8 L) werecautiously added monitoring gas evolution. THF was then removed invacuo, the residue was cooled to 0° C. and an aqueous 5M sodiumhydroxide solution was added until pH 9-10 had been reached. The aqueouslayer was extracted with Et₂O (3×1 L). Removal of solvent in vacuo gavethe title compound (140 g) as colorless oil.

MS (m/z): 228.1 [MH]⁺.

Preparation 4:(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4)

(S)-(+)-Mandelic acid (94 g) was added in portions to a stirred solutionof (1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Prep3, 140 g) in 1.4 L of THF. The resulting mixture was stirred atroom temperature for 2 h until a white precipitate was formed. Themixture was then warmed up to reflux temperature, stirred for 45 minutesand then slowly cooled down to room temperature. The white solid wascollected by filtration and dried in vacuo. This material wasrecrystallised 4 times from THF (10 volumes) to give 32.5 g of a whitesolid. This material was then suspended in sodium hydroxide (1Msolution, 400 mL) and Et₂O (400 mL) and allowed to stir at roomtemperature until complete dissolution. After separation of the twophases, the aqueous layer was extracted again with Et₂O (3×250 mL).Combined organic layers were washed with aqueous 1M sodium hydroxidesolution (3×200 mL) and then dried over Na₂SO₄. Evaporation of solventin vacuo gave the title compound (19 g) as white solid. The absoluteconfiguration of the optical isomers was assigned as described in PCTInternational Publication WO2005/080382.

NMR (¹H, CDCl₃): δ 7.51 (d, 2H), 7.25 (d, 2H), 3.20 (d, 1H), 3.0-3.1 (m,3H), 1.69 (m, 1H), 0.8-1.0 (m, 2H), NH not observed. MS (m/z): 228.1[MH]⁺.

Analytical Chromatography

Column: chiralcel OD 10 um, 250×4.6 mm

Mobile phase: A: n-Hexane; B: Isopropanol+0.1% Isopropyl amine

Gradient: isocratic 2% B

Flow rate: 1 mL/min

UV wavelength range: 200-400 nm

Analysis time 25 min

ret. time (min) % a/a 16.5 0.4 (1R,5S)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane 21.7 99.6 title compound

Specific Optical Rotation: [α]_(D)=−10° (CDCl₃, T=20° C., c≈0.004 g/0.8mL).

Preparation 5: 1-(4-chlorobutyl)-4-phenyl-2(1H)-pyrimidinone (Prep5)

The title compound was prepared using a similar procedure as set out inPCT Publication WO2004/080981.

MS (m/z): 207 [MH]+.

Preparation 6: 1-(4-chlorobutyl)-4-methyl-2(1H)-pyrimidinone (Prep6)

The title compound was prepared using a similar procedure as set out inthe PCT Publication WO2004/080981.

MS (m/z): 201 [MH]+.

Preparation 7: 5-Methyl-2-methylsulfanyl-3H-pyrimidin-4-one (Prep7)

A solution of 85% KOH (3.3 g, 50.7 mmol) and5-methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (7.2 g, 50.7 mmol) inabsolute EtOH (100 ml) was stirred for 1 hour and then MeI (7.2 g, 50.7mmol) was added dropwise. After refluxing the mixture for 2 hours, thesolvent was removed under vacuum. The residue was triturated with waterand the solid was filtered and dried in an oven to give 6.86 g of thetitle compound as a white powder (87% yield).

MS (ES) m/z 157.1 [M+H]⁺.

Preparation 8: 4-Chloro-5-methyl-2-methylsulfanyl-pyrimidine (Prep8)

A mixture of 5-methyl-2-methylsulfanyl-3H-pyrimidin-4-one (6.86 g, 44mmol) and POCl₃ (14 ml) in dioxane (60 ml) was refluxed for 2 hours. Thesolvent was removed under vacuum and the residue was quenched with iceand extracted with diethylether. The organic phase was dried (Na₂SO₄)and evaporated to give 6.8 g of the title compound as oil that was usedin the next step without further purification. (89% yield)

MS (ES) m/z 175.1 [M+H]⁺.

Preparation 9: 5-Methyl-2-methylsulfanyl-4-pyridin-3-yl-pyrimidine (Prep9)

A mixture of 4-chloro-5-methyl-2-methylsulfanyl-pyrimidine (1.24 g, 7.1mmol), pyridine-3-boroni acid (1.04 g, 8.46 mmol), Na₂CO₃ (863 mg, 7.76mmol), PPh₃ (186 mg, 0.71 mmol) and Pd(OAc)₂ (40 mg) in n-PrOH (50 ml)was refluxed for 2 hours. The solvent was then evaporated under vacuumand the crude was partitioned between water and ethyl acetate. Theorganic phase was dried (Na₂SO₄) and evaporated. The crude was purifiedby flash chromatography with ethyl acetate-petroleum ether (1-1) toafford 1.28 g of the title compound as a white solid (83% yield)

MS (ES) m/z 218.2 [M+H]⁺.

Preparation 10: 2-Methanesulfonyl-5-methyl-4-pyridin-3-yl-pyrimidine(Prep10)

A solution of 5-methyl-2-methylsulfanyl-4-pyridin-3-yl-pyrimidine (1.28g, 5.90 mmol) in MeOH (45 ml) was cooled at 0° C. and then an aqueoussolution of oxone (11 g, 17.95 mmol in 45 ml of water) was addeddropwise. After 15 minutes, ice bath was removed and the stirringcontinue for 3 hours. The mixture was neutralized with solid NaHCO₃ andthe product was extracted with ethyl acetate. The organic phase wasdried (Na₂SO₄) and evaporated to give 1.3 g of the title compound as awhite powder (88% yield).

MS (ES) m/z 250 [M+H]⁺.

Preparation 11: 5-Methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (Prep11)

2-Methanesulfonyl-5-methyl-4-pyridin-3-yl-pyrimidine (1.3 g, 5.22 mmol)was dissolved in dioxane (80 ml) and then 2N NaOH_(aq) (21 ml, 42 mmol)was added dropwise at room temperature. After stirring for 1 hour, thesolution was neutralized with 37% HCl_(aq). The residue was purified byflash chromatography with DCM-MeOH—NH₄OH (9-1-0.1) to give 951 mg of thetitle compound as a light brown powder. (97% yield).

MS (ES) m/z 188.2 [M+H]⁺.

Preparation 12:1-(4-Chloro-butyl)-5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (Prep12)

To a solution of 5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (100 mg,0.53 mmol) in DMSO (2 ml), 60% NaH (23 mg, 0.59 mmol) was addedportionwise. After heating the mixture at 60° C. for 1 hour,1-bromo-4-chloro-butane (100 mg, 0.59 mmol) dissolved in DMSO (0.8 ml)was added at 60° C. and the heating was maintained for further 2 hours.After cooling to room temperature, water was added and the mixtureextracted with diethyl ether to remove the dialkylated product andfinally with ethyl acetate. Ethyl acetate was washed with brine, dried(Na₂SO₄) and evaporated to afford 100 mg of the title compound as yellowoil (68% yield).

MS (ES) m/z 278 [M+H]⁺.

Preparation 13: 4-Iodo-2-methylsulfanyl-pyrimidine (Prep 13)

4-Chloro-2-methylsulfanyl-pyrimidine (2 ml, 17 mmol) and 57% HI_(aq)(15.46 ml) were mixed and stirred at room temperature for 2 days. Themixture was extracted with DCM and washed with a solution of NaS₂O₃ andthen with 5% NaHCO₃. The organic phase was dried (Na₂SO₄) and evaporatedto give 3.4 g of the title compound that was used in the next stepwithout further purification. (80% yield)

MS (ES) m/z 253.1 [M+H]⁺.

Preparation 14: 4-(6-Methyl-pyridin-2-yl)-2-methylsulfanyl-pyrimidine(Prep 14)

4-Iodo-2-methylsulfanyl-pyrimidine (1 g, 3.97 mmol) was dissolved in dryand degassed THF (9 ml). Pd(dba)₂ (114 mg, 0.20 mmol) andtri(2-furyl)phosphine (50 mg, 0.20 mmol) were added. The mixture wascooled at 0° C. and then a 0.5 M solution of 6-methyl-2-pyridylzincbromide in THF (13 ml, 6.5 mmol) was slowly added dropwise. Afterstirring the mixture at room temperature for 3 hours, ethyl acetate wasadded and the mixture was washed with water. The organic phase was dried(Na₂SO₄) and evaporated. The residue was purified by flashchromatography DCM-MeOH—NH₄OH (20-0.1-0.1) to give 785 mg of the titlecompound (90% yield).

MS (ES) m/z 218 [M+H]⁺.

Preparation 15: 2-Methanesulfonyl-4-(6-methyl-pyridin-2-yl)-pyrimidine(Prep15)

A solution of 4-(6-methyl-pyridin-2-yl)-2-methylsulfanyl-pyrimidine (785mg, 3.61 mmol) in MeOH (25 ml) was cooled at 0° C. and then an aqueoussolution of oxone (6.67 g, 10.85 mmol in 25 ml of water) was slowlyadded. After stirring 3 hours at room temperature, the mixture wasbasified with 5% NaHCO₃ and the product was extracted with ethylacetate. The organic phase was dried (Na₂SO₄) and evaporated to give 625mg of the title compound that was used in the next step without furtherpurification (70% yield).

MS (ES) m/z 250 [M+H]⁺.

Preparation 16: 4-(6-Methyl-pyridin-2-yl)-1H-pyrimidin-2-one (Prep16)

2-Methanesulfonyl-4-(6-methyl-pyridin-2-yl)-pyrimidine (625 mg, 2.51mmol) was dissolved in dioxane (20 ml) and then 2N NaOH_(aq) (12.5 ml,25 mmol) was added. After stirring at room temperature for 1 hour, thesolution was acidified with 37% HCl_(aq). The mixture was evaporated andthe residue redissolved in DCM-MeOH—NH₄OH (95-5-0.5) and evaporated. Thecrude was purified by Flash chromatography with DCM-MeOH (9-1) to give400 mg of the title compound. (85% yield).

MS (ES) m/z 188.2 [M+H]⁺.

Preparation 17:1-(4-Chloro-butyl)-4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (Prep17)

To a solution of 4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (200 mg,1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.39 mmol) was addedportionwise. After heating the mixture at 100° C. for 1 hour,1-bromo-4-chloro-butane (187 μl 1.39 mmol) was added and the mixture wasstirred overnight at room temperature. Water was added and the mixtureextracted with diethyl ether to remove the dialkylated product andfinally with ethyl acetate. Ethyl acetate was washed with brine, dried(Na₂SO₄) and evaporated. The residue was triturated with petroleum etherto give 173 mg of the title compound as a solid (58% yield).

MS (ES) m/z 278 [M+H]⁺.

Preparation 18: 4-Iodo-2-methylsulfanyl-pyrimidine (Prep 18)

4-Chloro-2-methylsulfanyl-pyrimidine (1 ml, 8.5 mmol) and 57% HI_(aq)(7.73 ml) were mixed and stirred at room temperature for 4 days. Themixture was extracted with DCM and washed with a solution of NaS₂O₃ andthen with 5% NaHCO₃. The organic phase was dried (Na₂SO₄) andevaporated, the residue was triturated with petroleum ether to give 1.57g of the title compound that was used in the next step without furtherpurification. (72% yield)

MS (ES) m/z 253.1 [M+H]⁺.

Preparation 19:4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrimidine(Prep19)

4-Iodo-2-methylsulfanyl-pyrimidine (453 mg, 1.79 mmol),2,2-difluoro-benzo[1,3]dioxole-4-boronic acid (727 mg, 3.59 mmol),Na₂CO₃ (380 mg, 3.59 mmol), 2-(dicyclohexylphosphino)biphenyl (125 mg,0.36 mmol) were suspended in degassed DME-water solution (5-1, 6.5 ml).After bubbling N₂ into the mixture for 20 minutes, Pd(PPh₃)₄ (413 mg,0.36 mmol) was added and the mixture was stirred at 90° C. for 3 hours.The solvent was evaporated under vacuum and the crude was dissolved inDCM and washed with water and brine. The organic phase was dried(Na₂SO₄) and evaporated; the crude was purified by flash chromatographywith hexane-ethyl acetate (8-2) to give the title compound (326 mg, 65%yield).

MS (ES) m/z 283.2 [M+H]⁺.

Preparation 20:4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrimidine(Prep20)

A solution of4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-methylsulfanyl-pyrimidine (326mg, 1.15 mmol) in MeOH (8 ml) was cooled at 0° C. and then an aqueoussolution of oxone (2.31 g, 3.76 mmol in 8 ml of water) was slowly added.After stirring 2 hours at room temperature, the mixture was basifiedwith 5% NaHCO₃ and the product was extracted with ethyl acetate. Theorganic phase was dried (Na₂SO₄) and evaporated to give 364 mg of thetitle compound that was used in the next step without furtherpurification (quantitative yield).

MS (ES) m/z 315 [M+H]⁺.

Preparation 21:4-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one (Prep 21)

4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrimidine (364mg, 1.15 mmol) was dissolved in dioxane (8.5 ml) and then 2N NaOH_(aq)(5.7 ml, 11 mmol) was added. After stirring at room temperature for 1hour, the solution was acidified with 37% HCl_(aq). The mixture wasevaporated and the residue was purified by flash chromatography withDCM-MeOH (9-1) to give 232 mg of the title compound. (quantitativeyield).

MS (ES) m/z 253 [M+H]⁺.

Preparation 22:1-(4-Chloro-butyl)-4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one(Prep22)

To a solution of4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one (232 mg, 0.92mmol) in dry DMF (18 ml), 60% NaH (47 mg, 1.19 mmol) was addedportionwise under inert atmosphere. After heating the mixture at 100° C.for 1 hour, 1-bromo-4-chloro-butane (137 μl 1.19 mmol) was added and themixture was stirred overnight at room temperature. Water was added andthe mixture extracted with diethyl ether. The organic layer was dried(Na₂SO₄) and evaporated. The residue purified by flash chromatographywith hexane-ethyl acetate (8-2) to give 123 mg of the title compound(39% yield).

MS (ES) m/z 343 [M+H]⁺.

Preparation 23: 4-Iodo-2-methylsulfanyl-pyrimidine (Prep23)

4-Chloro-2-methylsulfanyl-pyrimidine (1.04 ml, 9.0 mmol) and 57% HI_(aq)(10.56 ml) were mixed and stirred at room temperature for 18 hours. Themixture was extracted with DCM and washed with a solution of NaS₂O₃ andthen with 5% NaHCO₃. The organic phase was dried (Na₂SO₄) andevaporated; the residue was triturated with petroleum ether to give 1.82g of the title compound as a yellow solid (79% yield).

MS (ES) m/z 253.1 [M+H]⁺.

Preparation 24: 4-(2-Methyl-pyridin-3-yl)-2-methylsulfanyl-pyrimidine(Prep24)

To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (600 mg, 2.38 mmol),2-methylpyridine-3-boronic acid (533 mg, 3.09 mmol), Na₂CO₃ (756 mg,7.14 mmol), triphenylphosphine (62 mg, 0.24 mmol) in nPrOH (10 ml),Pd(OAc)₂ (16 mg, 0.07 mmol) was added and the mixture was stirred at 96°C. for 1.5 hours. The solvent was evaporated under vacuum, and the crudewas dissolved in DCM and washed with water. The organic phase was dried(Na₂SO₄) and evaporated. A second batch of this compound was preparedaccording to the same protocol starting from 0.45 mmol of4-iodo-2-methylsulfanyl-pyrimidine. The residues, deriving from the twobatches, were purified by flash chromatography with DCM-MeOH—NH₄OH(20-0.1-0.2) to give 568 mg of the title compound (92% yield).

MS (ES) m/z 218 [M+H]⁺.

Preparation 25: 2-Methanesulfonyl-4-(2-methyl-pyridin-3-yl)-pyrimidine(Prep25)

A solution of 4-(2-methyl-pyridin-3-yl)-2-methylsulfanyl-pyrimidine (530mg, 2.44 mmol) in MeOH (18 ml) was cooled at 0° C. and then an aqueoussolution of oxone (4.51 g, 7.32 mmol in 18 ml of water) was slowlyadded. After stirring 1.5 hours at room temperature, the mixture wasbasified with 5% NaHCO₃ and the product was extracted with ethylacetate. The organic phase was dried (Na₂SO₄) and evaporated to give 500mg of the title compound that was used in the next step without furtherpurification (80% yield).

MS (ES) m/z 250 [M+1-1]⁺.

Preparation 26: 4-(2-Methyl-pyridin-3-yl)-1H-pyrimidin-2-one (Prep 26)

2-Methanesulfonyl-4-(2-methyl-pyridin-3-yl)-pyrimidine (446 mg, 1.79mmol) was dissolved in dioxane (13 ml) and then 2N NaOH_(aq) (8.9 ml,17.9 mmol) was added. After stirring at room temperature for 1 hour, thesolution was acidified with 37% HCl_(aq). The mixture was evaporated andthe residue was re-dissolved in DCM-MeOH—NH₄OH (95-5-0.5) andevaporated. The crude was purified by flash chromatography with DCM-MeOH(9-1) to give 343 mg of the title compound. (quantitative yield).

MS (ES) m/z 188.2 [M+H]⁺.

Preparation 27:1-(4-Chloro-butyl)-4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (Prep27)

To a solution of 4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (199 mg,1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.38 mmol) was addedportionwise under inert atmosphere. After heating the mixture at 100° C.for 1 hour, 1-bromo-4-chloro-butane (160 μl, 1.38 mmol) was added andthe mixture was stirred at room temperature for 1 hour and heated at 70°C. for 2 hours. Water was added and the mixture extracted with diethylether and with ethyl acetate. The organic layers were mixed together,dried (Na₂SO₄) and evaporated to afford 161 mg of the title compoundthat was used in the next step without further purification (54% yield).

MS (ES) m/z 278 [M+H]⁺.

Preparation 28: 4-(2-Methyl-pyridin-4-yl)-2-methylsulfanyl-pyrimidine(Prep28)

To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (781 mg, 4.86mmol) in degassed nPrOH (55 ml), 2-methylpyridine-4-boronic acid (800mg, 5.84 mmol), Na₂CO₃ (619 mg, 5.47 mmol), triphenylphosphine (127 mg,0.486 mmol) and Pd(OAc)₂ (32 mg, 0.15 mmol) were added. The mixture wasstirred at 100° C. for 1 hour. The solvent was evaporated under vacuum,and the crude was dissolved in DCM and washed with water. The organicphase was dried (Na₂SO₄) and evaporated. The crude was purified by flashchromatography with DCM-MeOH—NH₄OH (20-0.1-0.2) to give 990 mg of thetitle compound (93% yield).

MS (ES) m/z 218 [M+H]⁺.

Preparation 29: 2-Methanesulfonyl-4-(2-methyl-pyridin-4-yl)-pyrimidine(Prep29)

A solution of 4-(2-methyl-pyridin-4-yl)-2-methylsulfanyl-pyrimidine (990mg, 4.56 mmol) in MeOH (35 ml) was cooled at 0° C. and then an aqueoussolution of oxone (8.41 g, 13.85 mmol in 35 ml of water) was slowlyadded. After stirring 3.5 hours at room temperature, the mixture wasbasified with solid NaHCO₃ and the product was extracted with ethylacetate. The organic phase was dried (Na₂SO₄) and evaporated to give 720mg of the title compound that was used in the next step without furtherpurification (65% yield).

MS (ES) m/z 250 [M+H]⁺.

Preparation 30: 4-(2-Methyl-pyridin-4-yl)-1H-pyrimidin-2-one (Prep30)

2-Methanesulfonyl-4-(2-methyl-pyridin-4-yl)-pyrimidine (720 mg, 2.89mmol) was dissolved in dioxane (25 ml) and then 2N NaOH_(aq) (14.4 ml,28.9 mmol) was added. After stirring at room temperature for 2 hours,the solution was acidified with 37% HCl_(aq). The mixture was evaporatedand the residue was re-dissolved in DCM-MeOH—NH₄OH (90-10-1) andevaporated. The crude was purified by flash chromatography with DCM-MeOH(9-1) to give 279 mg of the title compound. (52% yield).

MS (ES) m/z 188.2 [M+H]⁺.

Preparation 31:1-(4-Chloro-butyl)-4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (Prep31)

To a solution of 4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (256 mg,1.37 mmol) in dry DMF (45 ml), 60% NaH (71 mg, 1.78 mmol) was addedportionwise under inert atmosphere. After heating the mixture at 100° C.for 1 hour, 1-bromo-4-chloro-butane (305 mg, 1.78 mmol) was added andthe mixture was stirred at room temperature for 1.5 hours and heated at60° C. for 2 hours. Water was added and the mixture extracted withdiethyl ether and with ethyl acetate. The organic layers were mixedtogether, dried (Na₂SO₄) and evaporated to afford 100 mg of the titlecompound that was used in the next step without further purification inthe next step (27% yield).

MS (ES) m/z 278 [M+H]⁺.

Preparation 32: 4-Iodo-2-methylsulfanyl-pyrimidine (Prep32)

4-Chloro-2-methylsulfanyl-pyrimidine (1.04 ml, 9.0 mmol) and 57% HI_(aq)(10.56 ml) were mixed and stirred at room temperature for 48 hours. Themixture was extracted with DCM and washed with a solution of NaS₂O₃ andthen with 5% NaHCO₃. The organic phase was dried (Na₂SO₄) andevaporated; the residue was triturated with petroleum ether to give 1.82g of the title compound as a yellow solid (79% yield).

MS (ES) m/z 253.1 [M+H]⁺.

Preparation 33:4-(3,5-Dimethyl-isoxazol-4-yl)-2-methylsulfanyl-pyrimidine (Prep33)

To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (745 mg, 2.95 mmol)in degassed nPrOH (55 ml), 3,5-dimethyl-isoxazole-4-boronic acid (500mg, 3.54 mmol), Na₂CO₃ (375 mg, 3.54 mmol), triphenylphosphine (80 mg,0.29 mmol) and Pd(OAc)₂ (20 mg, 0.09 mmol) were added. The mixture wasstirred at 100° C. for 4.5 hours. The solvent was evaporated undervacuum, and the crude was dissolved in DCM and washed with water. Theorganic phase was dried (Na₂SO₄) and evaporated. The crude was purifiedby flash chromatography with petroleum ether-ethyl acetate (95-5 to 9-1)to give 638 mg of the title compound (97% yield).

MS (ES) m/z 222.2 [M+H]⁺.

Preparation 34:4-(3,5-Dimethyl-isoxazol-4-yl)-2-methanesulfonyl-pyrimidine (Prep34)

A solution of 4-(3,5-dimethyl-isoxazol-4-yl)-2-methylsulfanyl-pyrimidine(638 mg, 2.88 mmol) in MeOH (23 ml) was cooled at 0° C. and then anaqueous solution of oxone (5.31 g, 8.64 mmol in 23 ml of water) wasslowly added. After stirring 1.5 hours at room temperature, the mixturewas basified with solid NaHCO₃ and the product was extracted with ethylacetate. The organic phase was dried (Na₂SO₄) and evaporated to give 666mg of the title compound that was used in the next step without furtherpurification (91% yield).

MS (ES) m/z 254 [M+H]⁺.

Preparation 35: 4-(3,5-Dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one(Prep35)

4-(3,5-dimethyl-isoxazol-4-yl)-2-methanesulfonyl-pyrimidine (666 mg,2.63 mmol) was dissolved in dioxane (20 ml) and then 2N NaOH_(aq) (13.2ml, 26.3 mmol) was added. After stirring at room temperature for 30minutes, the solution was acidified with 37% HCl_(aq). The mixture wasevaporated and the residue was purified by flash chromatography withDCM-MeOH (9-1) to give the title compound. (quantitative yield).

MS (ES) m/z 192.2 [M+H]⁺.

Preparation 36:1-(4-Chloro-butyl)-4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one(Prep36)

To a solution of 4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one (156mg, 0.82 mmol) in dry DMF (20 ml), 60% NaH (40 mg, 1.06 mmol) was addedportionwise under inert atmosphere. After heating the mixture at 100° C.for 1 hour, 1-bromo-4-chloro-butane (123 μl, 1.06 mmol) was added atroom temperature and the mixture was heated at 100° C. for 2 hours.Water was added and the mixture extracted with diethyl ether to removethe dialkylated product and finally with ethyl acetate. Ethyl acetatephase was dried (Na₂SO₄) and evaporated to afford 81 mg of the titlecompound that was used in the next step without further purification(35% yield).

MS (ES) m/z 282 [M+H]⁺.

Preparation 37: 4-(2-Fluoro-phenyl)-2-methylsulfanyl-pyrimidine (Prep37)

To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (1.00 g, 6.22mmol), 2-fluoro-phenyl-boronic acid (1.04 g, 6.84 mmol), Na₂CO₃ (790 mg,7.45 mmol), triphenylphosphine (163 mg, 0.62 mmol) in nPrOH (50 ml),Pd(OAc)₂ (42 mg, 0.187 mmol) was added and the mixture was refluxed for3 hours. The solvent was evaporated under vacuum, and the crude wasdissolved in ethyl acetate and washed with water. The organic phase wasdried (Na₂SO₄) and evaporated; the crude was purified by flashchromatography with petroleum ether-ethyl acetate (97-3 to 95-5) to givethe title compound (1.23 g, 90% yield).

MS (ES) m/z 221 [M+H]⁺

Preparation 38: 4-(2-Fluoro-phenyl)-1H-pyrimidin-2-one (Prep38)

A solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine (943 mg,4.28 mmol) in 37%

HCl (18 ml) was heated at 100° C. for 21 hours. The mixture was dilutedwith water then basified with solid NaHCO₃. The suspension was extractedwith DCM; the organic layer was dried (Na₂SO₄), filtered and evaporatedto give the title compound that was used without further purification inthe next step (725 mg, 89% yield)

MS (ES) m/z 191 [M+H]+.

Preparation 39:1-[4-(tert-Butyl-dimethyl-silanyloxy)-butyl]-4-(2-fluoro-phenyl)-1H-pyrimidin-2-one(Prep39)

To a solution of 4-(2-fluoro-phenyl)-1H-pyrimidin-2-one (375 mg, 1.97mmol) in dry DMF (50 ml), 60% NaH (103 mg, 2.56 mmol) was addedportionwise. After heating the mixture at 100° C. for 1 hour,tert-butyl-(4-iodo-butoxy)-dimethyl-silane (664 μl 2.56 mmol) was addedat room temperature and the mixture was stirred overnight. Water wasadded and the mixture extracted with diethyl ether; the organic layerwas dried (Na₂SO₄), filtered and evaporated. The residue was purified byflash chromatography with petroleum ether-ethyl acetate (1-1) to give370 mg of the title compound as a yellow solid (50% yield).

MS (ES) m/z 377 [M+H]⁺.

Preparation 40:4-(2-Fluoro-phenyl)-1-(4-hydroxy-butyl)-1H-pyrimidin-2-one (Prep40)

1-[4-(tert-Butyl-dimethyl-silanyloxy)-butyl]-4-(2-fluoro-phenyl)-1H-pyrimidin-2-one(370 mg, 0.98 mmol) was dissolved in 4N HCl in dioxane (15 ml). Themixture was stirred at room temperature for 15 minutes, then basifiedwith 30% NH₄OH_(aq) and finally extracted with DCM. The organic layerwas dried (Na₂SO₄), filtered and evaporated, to give 258 mg of the titlecompound as a yellow solid (95% yield).

MS (ES) m/z 263 [M+H]⁺.

Preparation 41:4-[4-(2-Fluoro-phenyl)-2-oxo-2H-pyrimidin-1-yl]-butyraldehyde (Prep41)

To a solution of4-(2-fluoro-phenyl)-1-(4-hydroxy-butyl)-1H-pyrimidin-2-one (80 mg, 0.30mmol) in DCM (8 ml), the solution at 0° C., solid Dess Martinperiodinane (380 mg, 0.61 mmol) was added portionwise. The mixture wasstirred at room temperature for 1 hour. Na₂S₂O₃ was added and themixture was extracted with DCM; the organic layer was dried (Na₂SO₄),filtered and evaporated. The crude was purified by flash chromatographywith ethyl acetate to give 50 mg of the title compound as a green solid(64% yield).

MS (ES) m/z 261 [M+H]⁺.

Preparation 42: 2-Methylsulfanyl-4-pyridin-3-yl-pyrimidine (Prep42)

To a solution of 4-chloro-2-methylsulfanyl-pyrimidine (1.00 g, 6.22mmol), 3-pyridine-boronic acid (918 mg, 7.47 mmol), Na₂CO₃ (791 mg, 7.47mmol), triphenylphosphine (162 mg, 0.62 mmol) in nPrOH (60 ml), Pd(OAc)₂(41 mg, 0.19 mmol) was added and the mixture was stirred at 100° C. for1 hour. The solvent was evaporated under vacuum, and the crude wasdissolved in DCM and washed with water. The organic phase was dried(Na₂SO₄) and evaporated; the crude was purified by flash chromatographywith DCM-MeOH—NH₄OH (25-0.1-0.1 to 20-0.2-0.2) to give the titlecompound (1.18 g, 93% yield).

MS (ES) m/z 204.2 [M+H]⁺.

Preparation 43: 2-Methanesulfonyl-4-pyridin-3-yl-pyrimidine (Prep43)

A solution of 2-methylsulfanyl-4-pyridin-3-yl-pyrimidine (1.18 g, 5.81mmol) in MeOH (45 ml) was cooled at 0° C., then an aqueous solution ofoxone (10.7 g, 17.45 mmol in 45 ml of water) was slowly added. Afterstirring 1.5 hours at room temperature, the mixture was basified with 5%NaHCO₃ and the product was extracted with ethyl acetate. The organicphase was dried (Na₂SO₄) and evaporated to give 846 mg of the titlecompound that was used in the next step without further purification(61% yield).

MS (ES) m/z 236 [M+H]⁺.

Preparation 44: 4-Pyridin-3-yl-1H-pyrimidin-2-one (Prep44)

2-Methanesulfonyl-4-pyridin-3-yl-pyrimidine (846 mg, 3.58 mmol) wasdissolved in dioxane (36 ml) and then 2N NaOH_(aq) (18 ml, 36 mmol) wasadded. After stirring at room temperature for 1 hour, the solution wasacidified with 37% HCl_(aq). The mixture was evaporated and the residuewas re-dissolved in DCM-MeOH—NH₄OH (90-10-1) and evaporated. The residuewas purified by flash chromatography with DCM-MeOH (9-1) to give 500 mgof the title compound. (80% yield).

MS (ES) m/z 174.2 [M+H]⁺.

Preparation 45: 1-(4-Chloro-butyl)-4-pyridin-3-yl-1H-pyrimidin-2-one(Prep45)

To a solution of 4-pyridin-3-yl-1H-pyrimidin-2-one (50 mg, 0.29 mmol) indry DMF (11 ml), 60% NaH (15 mg, 0.37 mmol) was added portionwise underinert atmosphere. After heating the mixture at 100° C. for 1 hour,1-bromo-4-chloro-butane (43 μl, 0.37 mmol) was added at room temperatureand the mixture was stirred overnight. Water was added and the mixtureextracted with diethyl ether to remove the dialkylated product andfinally with ethyl acetate. Ethyl acetate was washed with brine, dried(Na₂SO₄) and evaporated to give 40 mg of the title compound as a solid(54% yield).

MS (ES) m/z 264.1 [M+H]⁺.

Preparation 46: 4-Iodo-2-methylsulfanyl-pyrimidine (Prep46)

4-Chloro-2-methylsulfanyl-pyrimidine (0.75 ml, 6.2 mmol) and 57% HI_(aq)(5.6 ml) were mixed and stirred at room temperature for 48 hours. Themixture was extracted with DCM and washed with a solution of NaS₂O₃ andthen with 5% NaHCO₃. The organic phase was dried (Na₂SO₄) andevaporated, the residue was triturated with petroleum ether to give 1.30g of the title compound that was used in the next step without furtherpurification (83% yield).

MS (ES) m/z 253.1 [M+H]⁺

Preparation 47:4-(2,4-Dimethyl-thiazol-5-yl)-2-methylsulfanyl-pyrimidine (Prep47)

To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (390 mg, 1.56 mmol),2,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole(633 mg, 2.65 mmol added portionwise), Na₂CO₃ (215 mg, 2.02 mmol),triphenylphosphine (42 mg, 0.15 mmol) in nPrOH (25 ml), Pd(OAc)₂ (11 mg,0.047 mmol) was added and the mixture was refluxed for 2 hour. Thesolvent was evaporated under vacuum, and the crude was dissolved in DCMand washed with water. The organic phase was dried (Na₂SO₄) andevaporated. A second batch of this compound was prepared according tothe same protocol starting from 0.39 mmol of4-iodo-2-methylsulfanyl-pyrimidine. The residues, deriving from the twobatches, were purified by flash chromatography with hexane-ethyl acetateto give the title compound (352, 76% yield).

MS (ES) m/z 238.2 [M+H]⁺.

Preparation 48:4-(2,4-Dimethyl-thiazol-5-yl)-2-methanesulfonyl-pyrimidine (Prep48)

A solution of 4-(2,4-dimethyl-thiazol-5-yl)-2-methylsulfanyl-pyrimidine(342 mg, 1.44 mmol) in MeOH (12 ml) was cooled at 0° C., then an aqueoussolution of oxone (2.65 g, 4.32 mmol in 12 ml of water) was slowlyadded. After stirring 2 hours at room temperature, the mixture wasbasified with 5% NaHCO₃ and the product was extracted with ethylacetate. The organic phase was dried (Na₂SO₄) and evaporated to give 288mg of the title compound that was used in the next step without furtherpurification (75% yield).

MS (ES) m/z 270.3 [M+H]⁺.

Preparation 49: 4-(2,4-Dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one(Prep49)

4-(2,4-dimethyl-thiazol-5-yl)-2-methanesulfonyl-pyrimidine (288 mg, 1.07mmol) was dissolved in dioxane (13 ml) and then 2N NaOH_(aq) (6 ml, 12mmol) was added. After stirring at room temperature for 1 hour, thesolution was acidified with 37% HCl_(aq). The mixture was evaporated andthe residue was purified by flash chromatography with DCM-MeOH (9-1) togive 166 mg of the title compound. (75% yield).

MS (ES) m/z 208.2 [M+H]⁺.

Preparation50:1-(4-Chloro-butyl)-4-(2,4-dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one(Prep50)

To a solution of 4-(2,4-Dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one (120mg, 0.58 mmol) in dry DMF (21 ml), 60% NaH (24 mg, 0.75 mmol) was addedportionwise under inert atmosphere. After heating the mixture at 100° C.for 1 hour, 1-bromo-4-chloro-butane (86 μl, 0.75 mmol) was added at roomtemperature and the mixture was stirred overnight then was heated at 69°C. for 2 hours. Water was added and the mixture extracted with diethylether to remove the dialkylated product and finally with ethyl acetate.Ethyl acetate was washed with brine, dried (Na₂SO₄) and evaporated togive 80 mg of the title compound as a solid (48% yield).

MS (ES) m/z 298.1 [M+H]⁺.

Preparation 51: 1-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinone (Prep51)

To a suspension of 5-phenyl-2(1H)-pyrimidinone (77 mg, 0.45 mmol, AuroraScreening Library or MDPI Product List or ref Helv. Chim. Acta, 10,1927, 305//Collect. Czech. Chem. Commun., 61, 3, 1996, 458-477) in drydichloromethane (4.0 ml), triethylamine (0.062 ml, 0.45 mmol) was added.The reaction mixture was stirred at room temperature for 30′, then1-bromo-4-chlorobutane (0.052 ml, 0.44 mmol) was added and the reactionmixture was then heated at 40° C. for 24 hours and other 24 hours at 60°C. Water (22 ml) was added to the cold mixture and the organic layerswere extracted with DCM (3×10 ml). The organic layers were combined anddried over Na₂SO₄, filtered and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel eluting withDCM/methanol 96/4 to afford the title compound (60 mg, 51%).

¹H-NMR (CHLOROFORM-d) δ ppm 8.81-8.94 (m, 1H) 7.82-7.91 (m, 1H)7.35-7.59 (m, 5H) 4.03 (t, 2H) 3.61 (t, 2H) 1.99-2.12 (m, 2H) 1.80-1.96(m, 2H)

Example 14-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E1)

A mixture of 1-(4-chlorobutyl)-4-phenyl-2(1H)-pyrimidinone (Prep5, 52mg), (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane(Prep4, 30 mg), K₂CO₃ (36 mg) and NaI (33 mg) in DMF (anhydrous, 0.5 mL)was heated at 70° C. for 18 h. After elimination of the solvent underreduced pressure, the residue was dissolved in EtOAc and the organiclayer was washed with water and dried over Na₂SO₄. This solution wasfiltered and the filtrate was concentrated in vacuo. The crude waspurified by flash chromatography (dichloromethane to 5% MeOH/0.5%NH3_(acq) in DCM) to give 45 mg of the free base of the title compound.To a solution of this material in DCM (0.2 mL) was added 0.1 mmol of HCl(1M solution in Et₂O), the solvent evaporated under vacuo and thematerial obtained triturated with Et₂O to give 40 mg of the titlecompound as a white slightly hygroscopic solid (62% yield).

1H NMR (DMSO-d₆) ppm 1.16-1.23 (m, 1H) 1.62-1.68 (m, 1H) 1.69-1.79 (m,4H) 2.25-2.32 (m, 1H) 3.19-3.28 (m, 2H) 3.46-3.54 (m, 1H) 3.60-3.66 (m,1H) 3.70 (dd, 1H) 3.89-3.94 (m, 2H) 4.04 (dd, 1H) 7.12 (d, 1H) 7.48 (d,2H) 7.53 (t, 2H) 7.55-7.61 (m, 1H) 7.70 (d, 2H) 8.12 (d, 2H) 8.32 (d,1H) 10.27 (br. s., 1H). MS (m/z): 491[MH]⁺.

Example 24-methyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-3,4-dihydro-2(1H)-pyrimidinonehydrochloride (E2)

The title compound was prepared using a similar procedure as set outearlier in Example 1, from(1S,5R/1R,5S)-1-(4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexane(Prep4, 40 mg) and 1-(4-chlorobutyl)-4-methyl-2(1H)-pyrimidinone (Prep6,52 mg) heating at 90° C. for 18 h, in 36 mg yield as a white slightlyhygroscopic solid.

¹H NMR (DMSO-d6) ppm 1.15-1.30 (m, 1H) 1.52-1.85 (m, 5H) 2.17-2.38 (m,1H) 2.29 (s, 3H) 3.09-3.47 (m, 2H) 3.45-3.57 (m, 1H) 3.59-3.69 (m, 1H)3.67-3.77 (m, 1H) 3.80-3.91 (m, 2H) 3.98-4.10 (m, 1H) 6.40 (d, 1H) 7.49(d, 2H) 7.72 (d, 2H) 8.12 (d, 1H) 10.24 (br. s., 1H). MS (m/z):392[MH]⁺.

Example 35-methyl-4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E3)

A solution of1-(4-chloro-butyl)-5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (Prep12,86 mg, 0.31 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,63 mg, 0.28 mmol), KI (2 mg) and K₂CO₃ (43 mg, 0.31 mmol) in DMF (2 ml)was placed in a microwave oven and irradiated at 115° C. for 1 hour.After cooling, the solution was diluted with water and extracted withethyl acetate. The organic layer was washed with brine, dried (Na₂SO₄)and evaporated The solvent was removed under vacuum and the residue wasredissolved in DCM and filtered, the filtrate was stirred in thepresence of PS-isocyanate (350 mg) for 3 hours. The mixture was filteredand the solvent removed under vacuum. The crude was purified by flashchromatography with DCM-MeOH—NH₄OH (99-1-0.1) to give the title compound(17 mg, 4% yield) as a free base.

5-Methyl-4-pyridin-3-yl-1-[4-((1S,5R)-1-p-tolyl-3-aza-bicyclo[3.1.0]hex-3-yl)-butyl]-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) m/z 469.2 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 11.07 (br. s., 1H), 9.00 (s, 1H), 8.90(d, 1H), 8.44 (s, 1H), 8.46 (d, 1H), 7.90 (dd, 1H), 7.70 (m, 2H), 7.50(m, 2H), 4.03 (dd, 1H), 3.95 (t, 2H), 3.58-3.75 (m, 2H), 3.44-3.56 (m,1H), 3.18-3.35 (m, 2H), 2.21-2.36 (m, 1H), 2.10 (s, 3H), 1.90 (dd, 0H),1.70-1.87 (m, 4H), 1.18 (dd, 1H)

Example 44-(6-methyl-2-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonedihydrochloride (E4)

A solution of1-(4-chloro-butyl)-4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (Prep17,48 mg, 0.17 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,38 mg, 0.17 mmol), KI (2 mg) and DIPEA (66 mg, 0.51 mmol) in absoluteEtOH (2 ml) was placed in a microwave oven and irradiated at 125° C. for13 hours. The solvent was removed under vacuum and the residue wasredissolved in DCM and filtered. The filtrate was stirred in thepresence of PS-isocyanate (350 mg) for 3 hours. The mixture was filteredand the solvent removed under vacuum. The crude was purified by flashchromatography with DCM-MeOH—NH₄OH (99-1-0.1) to give the title compound(17 mg, 4% yield) as a free base.

4-(6-Methyl-pyridin-2-yl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (2 eq), to give the title compound.

MS (ES) m/z 469.26 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.30 (br. s., 1H), 8.38 (d, 1H), 8.15(d, 1H), 7.92 (dd, 1H), 7.69 (m, 2H), 7.44-7.54 (m, 3H), 7.39 (d, 1H),4.05 (dd, 1H), 3.86-4.01 (m, 2H), 3.59-3.80 (m, 2H), 3.43-3.59 (m, 1H),3.25 (br. s., 2H), 2.59 (s, 3H), 2.22-2.35 (m, 1H), 1.70-1.82 (m, 4H),1.64 (dd, 1H), 1.20 (dd, 1H)

Example 54-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E5)

A solution of1-(4-chloro-butyl)-4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-1H-pyrimidin-2-one(Prep22, 123 mg, 0.36 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,81 mg, 0.36 mmol), KI (2 mg) and TEA (150 μl, 1.08 mmol) in absoluteEtOH (4 ml) was heated at 90° C. for 48 hours. The solvent was removedunder vacuum and the residue was redissolved in DCM and stirred in thepresence of PS-isocyanate for 2 hours. The mixture was filtered and thesolvent removed under vacuum. The crude was finally purified bypreparative LC-MS. The so obtained trifluoroacetate salt was passed overSCX cartridge affording 46 mg of free base of the title compound (24%yield).

4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) m/z 534.24 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.46 (br. s., 1H), 8.40 (d, 1H), 7.88(dd, 1H), 7.69 (m, 2H), 7.62 (dd, 1H), 7.49 (m, 2H), 7.37 (dd, 1H), 6.97(d, 1H), 4.05 (dd, 1H), 3.90-4.00 (m, 2H), 3.59-3.81 (m, 2H), 3.41-3.59(m, 1H), 3.19-3.31 (m, 2H), 2.16-2.31 (m, 1H), 1.76 (br. s., 4H),1.65-1.73 (m, 1H), 1.09-1.32 (m, 1H).

Example 64-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E6)

A solution of1-(4-chloro-butyl)-4-(2-methyl-pyridin-3-yl)-1H-pyrimidin-2-one (Prep27,161 mg, 0.58 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,132 mg, 0.58 mmol), and K₂CO₃ (79 mg, 0.58 mmol) in DMF (4 ml) wasplaced in a microwave oven and heated at 120° C. for 90 minutes. Thesolvent was removed under vacuum and the residue was redissolved inethyl acetate and washed with water. The organic layers was dried(Na₂SO₄) and evaporated. The crude was purified by preparative LC-MS.The so obtained trifluoroacetate salt was passed over SCX cartridge toafford 20 mg of the title compound (7% yield) as a free base.

4-(2-Methyl-pyridin-3-yl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) m/z 469.26 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.95 (br. s., 1H), 8.85 (dd, 1H),8.42-8.58 (m, 2H), 7.92 (dd, 1H), 7.70 (m, 2H), 7.50 (m, 2H), 6.85 (d,1H), 4.04 (dd, 1H), 3.92-4.00 (m, 2H), 3.58-3.78 (m, 2H), 3.42-3.56 (m,1H), 3.12-3.33 (m, 2H), 2.81 (s, 3H), 2.18-2.38 (m, 1H), 1.65-1.92 (m,5H), 1.11-1.23 (m, 1H).

Example 74-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E7)

A solution of1-(4-chloro-butyl)-4-(2-methyl-pyridin-4-yl)-1H-pyrimidin-2-one (Prep31,100 mg, 0.36 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,78 mg, 0.34 mmol), KI (3 mg) and K₂CO₃ (52 mg, 0.38 mmol) in DMF (1.5ml) was placed in a microwave oven and heated at 120° C. for 90 minutes.Water was added and the product was extracted with ethyl acetate. Theorganic layers was washed with brine, dried (Na₂SO₄) and evaporated. Thecrude was purified by preparative HPLC. The so obtained trifluoroacetatesalt was passed over SCX cartridge to afford 70 mg of the title compound(41% yield) as a free base.

4-(2-Methyl-pyridin-4-yl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) m/z 469.12 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 11.35 (br. s., 1H), 8.73 (d, 1H), 8.47(d, 1H), 8.14 (s, 1H), 8.05 (d, 1H), 7.67 (m, 2H), 7.51 (m, 2H), 7.13(d, 1H), 3.88-4.18 (m, 3H), 3.64 (br. s., 3H), 3.09-3.35 (m, 2H), 2.71(s, 3H), 2.17-2.31 (m, 1H), 2.01 (t, 1H), 1.84 (br. s., 4H), 1.11-1.24(m, 1H).

[α]²⁰ _(D)-37.8 (c=0.45, MeOH)

Example 84-(3,5-dimethyl-4-isoxazolyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E8)

A solution of1-(4-chloro-butyl)-4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one(Prep36, mg, 0.28 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,53 mg, 0.23 mmol) and K₂CO₃ (40 mg, 0.28 mmol) in DMF (2.5 ml) wasplaced in a microwave oven and heated at 120° C. for 2 hours. Water wasadded and the product was extracted with ethyl acetate. The organiclayers was washed with brine, dried (Na₂SO₄) and evaporated. A secondbatch of this compound was prepared according to the same protocolstarting from 0.19 mmol of1-(4-chloro-butyl)-4-(3,5-dimethyl-isoxazol-4-yl)-1H-pyrimidin-2-one.The residues, deriving from the two batches were purified by preparativeLC-MS. The so obtained trifluoroacetate salt was passed over SCXcartridge to afford title compound as a free base.4-(3,5-Dimethyl-isoxazol-4-yl)-1-[4-((1S,5R)-1-p-tolyl-3-aza-bicyclo[3.1.0]hex-3-yl)-butyl]-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give 10 mg of the titlecompound (4% yield).

MS (ES) m/z 473.17 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.94 (br. s., 1H), 8.31 (d, 1H), 7.70(m, 2H), 7.49 (m, 2H), 6.65 (d, 1H), 4.03 (dd, 1H), 3.84-3.95 (m, 2H),3.58-3.74 (m, 3H), 3.18-3.28 (m, 2H), 2.64 (s, 3H), 2.41 (s, 3H),2.23-2.32 (m, 1H), 1.84-1.90 (m, 1H), 1.66-1.84 (m, 4H), 1.07-1.26 (m,1H)

Example 94-(2-fluorophenyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E9)

4-[4-(2-Fluoro-phenyl)-2-oxo-2H-pyrimidin-1-yl]-butyraldehyde (Prep41,50 mg, 0.19 mmol) was dissolved in DCE (5.5 ml). The resulting solutionwas cooled at 0° C. and then(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,53 mg, 0.23 mmol), AcOH (13 μl) and NaBH(AcO)₃ (45 mg, 0.21 mmol) wereadded. The mixture was stirred for 10 minutes at 0° C. 1N NaOH_(aq) wasadded and the product was extracted with DCM. The organic phase wasdried (Na₂SO₄) and evaporated. The crude was purified by flashchromatography with DCM-MeOH—NH₄OH (20-0.2-0.2) to give 52 mg of thetitle compound (58% yield) as a free base.

4-(2-Fluoro-phenyl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas dissolved in dioxane and treated with 4N HCl in dioxane (1 eq), togive after trituration with iPr₂O, the title compound as a powder.

MS (ES) m/z 472.08 [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 11.02 (br. s., 1H), 8.37 (d, 1H), 7.94(td, 1H), 7.69 (m, 2H), 7.57-7.66 (m, 1H), 7.49 (m, 2H), 7.29-7.43 (m,2H), 6.86 (dd, 1H), 3.99-4.04 (m, 1H), 3.88-3.97 (m, 2H), 3.45-3.77 (m,3H), 3.09-3.32 (m, 1H), 2.11-2.39 (m, 1H), 1.89 (dd, 1H), 1.68-1.85 (m,4H), 1.17 (dd, 1H). [α]²⁰ _(D)-38.2 (c=0.315, MeOH)

Example 104-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E10)

A solution of 1-(4-chloro-butyl)-4-pyridin-3-yl-1H-pyrimidin-2-one(Prep45, 38 mg, 0.14 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4,29 mg, 0.13 mmol), KI (2 mg) and K₂CO₃ (20 mg, 0.14 mmol) in DMF (1 ml)was placed in a microwave oven and irradiated at 100° C. for 45 minutes.Water was added and the mixture extracted with ethyl acetate. Theorganic layer was dried (Na₂SO₄), filtered and evaporated. The crude waspurified by preparative LC-MS. The so obtained trifluoroacetate salt waspassed over SCX cartridge to afford 22 mg of the title compound (34%yield) as a free base.

4-Pyridin-3-yl-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewith 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) 455.18 m/z [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.99 (br. s., 1H), 9.43 (br. s., 1H),8.94 (br. s., 1H), 8.86 (d, 1H), 8.52 (d, 1H), 7.84-8.05 (m, 1H), 7.69(m, 2H), 7.49 (m, 2H), 7.28 (d, 1H), 4.03 (dd, 1H), 3.90-3.99 (m, 2H),3.42-3.75 (m, 3H), 3.12-3.33 (m, 1H), 2.18-2.38 (m, 1H), 1.83-1.91 (m,1H), 1.70-1.83 (m, 4H), 1.08-1.22 (m, 1H)

Example 114-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinonehydrochloride (E11)

A solution of1-(4-chloro-butyl)-4-(2,4-dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one(Pre50, 80 mg, 0.27 mmol),(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Pre4,55 mg, 0.24 mmol) and K₂CO₃ (37 mg, 0.27 mmol) in dry DMF (2.5 ml) wasplaced in a microwave oven and irradiated at 115° C. for 2 hours. Waterwas added and the mixture extracted with ethyl acetate. The organiclayer was dried (Na₂SO₄), filtered and evaporated. The crude waspurified by preparative LC-MS. The so obtained trifluoroacetate salt waspassed over SCX cartridge to afford 23 mg of the title compound (17%yield) as a free base.

4-(2,4-Dimethyl-thiazol-5-yl)-1-{4-[(1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hex-3-yl]-butyl}-1H-pyrimidin-2-onewas treated with 4N HCl in dioxane (1 eq), to give the title compound.

MS (ES) 489.07 m/z [M+H]⁺.

¹H-NMR (DMSO-d₆, TFA, 300 MHz) δ: 10.79 (br. s., 1H), 8.29 (d, 1H), 7.69(m, 2H), 7.49 (m, 2H), 6.75 (d, 1H), 4.03 (dd, 1H), 3.89 (dd, 2H),3.56-3.76 (m, 2H), 3.43-3.56 (m, 1H), 3.14-3.29 (m, 2H), 2.64 (s, 6H),2.19-2.36 (m, 1H), 1.58-1.90 (m, 5H), 1.09-1.28 (m, 1H)

Example 125-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone(E12)

To a solution of(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (52 mg,0.23 mmol, prepared with a similar procedure to that reported in WO2005080382) in N,N-dimethylformamide (DMF) (3 ml) were added at roomtemperature 1-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinone (Prep51, 60.1mg, 0.23 mmol, D1) and triethylamine (0.064 ml, 0.46 mmol). The reactionmixture was heated at 100° C. for 24 hours, then passed through a SCXcartridge (10 g) (eluting with methanol followed by 2N ammonia solutionin methanol). The crude obtained was then purified by columnchromatography on silica gel eluting with DCM/methanol 96/4. Afterevaporation of the solvent the compound recovered (20 mg, 0.044 mmol)was dissolved in DCM (1 ml) and treated with HCl (1.1 eq of a 1.25 Msolution in methanol, 0.048 mmol). The resulting mixture was stirred atroom temperature for 0.5 hour. Evaporation of the solvent andtrituration with diethyl ether (2×3 ml) gave the hydrochloride salt ofthe title compound. The recovered material was passed through SCX (2 g)cartridge (eluting with methanol followed by 2N ammonia solution inmethanol) to recover (6 mg, 0.013 mmol) of the title compound.

MS (ES) m/z: 454 [MH⁺]

¹H-NMR(CHLOROFORM-d) δ ppm 8.89 (d, 1H) 7.82 (d, 1H) 7.54 (d, 2H)7.38-7.51 (m, 5H) 7.22 (d, 2H) 4.03 (t, 2H) 3.27-3.48 (m, 1H) 3.04-3.21(m, 1H) 2.39-2.71 (m, 4H) 1.86-2.01 (m, 2H) 1.71-1.83 (m, 1H) 1.46-1.65(m, 3H) 0.77-0.92 (m, 1H)

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It is to be understood that the present invention covers allcombinations of particular groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1-11. (canceled)
 12. Compound of formula (I)′ or a salt thereof:

wherein G is selected from the group consisting of: phenyl, a 5- or6-membered monocyclic heteroaryl group, or a 8- to 11-memberedheteroaryl bicyclic group; A is a group P wherein P is

p is an integer ranging from 0 to 5; R₁ is halogen, hydroxy, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andSF₅; or corresponds to a group R₆; and when p is an integer ranging from2 to 5, each R₁ may be the same or different; R₂ is hydrogen orC₁₋₄alkyl; n is 4, 5 or 6; R₃ is selected in the group consisting of:hydrogen, halogen, cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₃ is a phenylgroup, a 5-14 membered heterocyclic group; and any of such phenyl orheterocyclic group is optionally substituted by 1, 2, 3 or 4substituents selected from the group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅ andhaloC₁₋₄alkoxy; and wherein such haloC₁₋₄alkoxy substituents, whereinplaced in adjacent positions, may for, together with the carbon atoms towhich they're attached a 5 or 6-membered unsaturated heterocyclic ring;R₄ is selected in the group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, C₃₋₇cycloalkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₄ is a phenyl group, a 5-14membered heterocyclic group; and any of such phenyl or heterocyclicgroup is optionally substituted by 1, 2, 3 or 4 substituents selectedfrom the group consisting of: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; R₅ is selected from the groupconsisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl, C₃₋₇cycloalkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andNR′R″; or R₅ is a phenyl group, a 5-14 membered heterocyclic group; andany of such phenyl or heterocyclic group is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; R₆ isa moiety selected from the group consisting of: isoxazolyl,—CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl,pyridyl, 2-pyrrolidinonyl, and such R₆ group is optionally substitutedby one or two substituents selected from: halogen, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl; R₇ is hydrogen or C₁₋₂ alkyl;R′ is H, C₁₋₄alkyl or C₁₋₄alkanoyl; R″ is defined as R′; R′ and R″ takentogether with the interconnecting nitrogen atom may form a 5-,6-membered saturated or unsaturated heterocyclic ring; wherein at leastone of R₄ and R₅ is hydrogen; and wherein only one R₂ group may bedifferent from hydrogen.
 13. A compound of formula (IA)

wherein G is selected from the group consisting of: phenyl, a 5- or6-membered monocyclic heteroaryl group, or a 8- to 11-memberedheteroaryl bicyclic group; A is a group P wherein P is

p is an integer ranging from 0 to 5; R₁ is halogen, hydroxy, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andSF₅; or corresponds to a group R₆; and when p is an integer ranging from2 to 5, each R₁ may be the same or different; R₂ is hydrogen orC₁₋₄alkyl; n is 4, 5 or 6; R₃ is selected in the group consisting of:hydrogen, halogen, cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₃ is a phenylgroup, a 5-14 membered heterocyclic group; and any of such phenyl orheterocyclic group is optionally substituted by 1, 2, 3 or 4substituents selected from the group consisting of: halogen, cyano,C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, SF₅ andhaloC₁₋₄alkoxy; and wherein such haloC₁₋₄alkoxy substituents, whereinplaced in adjacent positions, may for, together with the carbon atoms towhich they're attached a 5 or 6-membered unsaturated heterocyclic ring;R₄ is selected in the group consisting of: hydrogen, halogen, hydroxy,cyano, C₁₋₄alkyl, C₃₋₇ cycloalkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkanoyl and NR′R″; or R₄ is a phenyl group, a 5-14membered heterocyclic group; and any of such phenyl or heterocyclicgroup is optionally substituted by 1, 2, 3 or 4 substituents selectedfrom the group consisting of: halogen, cyano, C₁₋₄alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; R₅ is selected from the groupconsisting of: hydrogen, halogen, hydroxy, cyano, C₁₋₄alkyl, C₃₋₇cycloalkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkanoyl andNR′R″; or R₅ is a phenyl group, a 5-14 membered heterocyclic group; andany of such phenyl or heterocyclic group is optionally substituted by 1,2, 3 or 4 substituents selected from the group consisting of: halogen,cyano, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl and SF₅; R₆ isa moiety selected from the group consisting of: isoxazolyl,—CH₂—N-pyrrolyl, 1,1-dioxido-2-isothiazolidinyl, thienyl, thiazolyl,pyridyl, 2-pyrrolidinonyl, and such R₆ group is optionally substitutedby one or two substituents selected from: halogen, cyano, C₁₋₄alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl; R₇ is hydrogen or C₁₋₂ alkyl;R′ is H, C₁₋₄alkyl or C₁₋₄alkanoyl; R″ is defined as R′; R′ and R″ takentogether with the interconnecting nitrogen atom may form a 5-,6-membered saturated or unsaturated heterocyclic ring; wherein at leastone of R₄ and R₅ is hydrogen; and wherein only one R₂ group ma bedifferent from hydrogen.
 14. A compound according to claim 13 selectedfrom the group consisting of:5-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(2,4-dimethyl-1,3-thiazol-5-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(2-fluorophenyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(3,5-dimethyl-4-isoxazolyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-(6-methyl-2-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;5-methyl-4-(3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;4-methyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-3,4-dihydro-2(1H)-pyrimidinone;4-phenyl-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2(1H)-pyrimidinone;and salts thereof.
 15. A method of treating a condition for whichmodulation of dopamine D₃ receptors is beneficial, which comprisesadministering to a patient in need thereof an effective amount of acompound of formula (I)′ according to claim 12, neat or admixed with apharmaceutically acceptable carrier.
 16. A method as claimed in claim 15wherein the condition is psychosis or a psychotic condition, substanceabuse or premature ejaculation.
 17. A pharmaceutical compositioncomprising a compound of formula (I)′ according to claim 1 or apharmaceutically acceptable salt thereof admixed with a pharmaceuticallyacceptable carrier.
 18. A method of treating a condition for whichmodulation of dopamine D₃ receptors is beneficial, which comprisesadministering to a patient in need thereof an effective amount of acompound of formula (IA) according to claim 13, neat or admixed with apharmaceutically acceptable carrier.
 19. A method as claimed in claim 18wherein the condition is psychosis or a psychotic condition, substanceabuse or premature ejaculation.
 20. A pharmaceutical compositioncomprising a compound of formula (IA) according to claim 13 or apharmaceutically acceptable salt thereof admixed with a pharmaceuticallyacceptable carrier.